Long-acting polymeric delivery systems

ABSTRACT

Compositions comprised of a delivery vehicle or delivery system and an active agent dispersed within the delivery vehicle or system, wherein the delivery vehicle or system contains a polyorthoester polymer and a polar aprotic solvent. Also disclosed are low viscosity delivery systems for administration of active agents. The low viscosity delivery systems have a polyorthoester polymer, a polar aprotic solvent and a solvent containing a triglyceride viscosity reducing agent. Compositions described include an amide- or anilide-type local anesthetic of the “caine” classification, and a non-steroidal anti-inflammatory drug (NSAID), along with related methods, e.g., for treatment of post-operative pain or for prophylactic treatment of pain. The compositions are suitable for delivery via, e.g., direct application and instillation, intradermal injection, subcutaneous injection, and nerve block (perineural).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 14/691,464 filed Apr. 20, 2015, which claims the benefit of U.S.Provisional Application No. 61/982,314 filed Apr. 21, 2014, and of U.S.Provisional Application No. 61/996,788 filed May 14, 2014, and of U.S.Provisional Application No. 62/131,797 filed Mar. 11, 2015, each ofwhich is incorporated herein in its entirety.

TECHNICAL FIELD

The present disclosure is directed to compositions for delivery ofpharmaceutically active agents to subjects in need thereof. In oneembodiment, compositions disclosed herein provide delivery of one ormore active agents over a period of up to about eight days. Exemplarycompositions are formulated for the treatment and management of pain,such as post-operative pain, or for the treatment or prophylactictreatment of emesis.

BACKGROUND

Optimizing the time release profile for delivery of therapeutic agentsafter administration to a patient is a primary consideration whenformulating pharmaceuticals for use in the medical community. Theadministered formulation can significantly affect both the duration ofthe drug release and delivery to a patient, as well as the ability ofthe active agent to remain in the body to provide its intendedtherapeutic effect. Depending on the condition being treated, it may benecessary to provide rapid delivery over a relatively short period oftime or extended release for long term treatment without theinconvenience of repeated administrations. Regardless, the ultimate goalis often to provide optimal therapeutic benefit with minimal adverseside effects.

Pain is defined by the International Association for the Study of Pain(IASP) as an unpleasant sensory and emotional experience associated withactual or potential tissue damage, or described in terms of such damage(Classification of Chronic Pain, 2^(nd) Ed., Eds. Merkskey & Bogduk,IASP Press, 1994). An effective pain treatment modality is generallyconsidered to be one which provides relief of pain with minimal adverseand/or unwanted side-effects. Treatment of acute pain, such aspost-operative pain following surgery, is an area of activeinvestigation. Indeed, the effective treatment of post-operative pain isnow considered to be an essential component of the overall care of asurgical patient.

Surgical pain is generally due to inflammation from tissue trauma (e.g.,due to the surgical incision, dissection or burns) or direct nerveinjury (e.g., nerve transection, stretching, or compression). Painrelief is of primary importance to almost every patient undergoingsurgery and to medical personnel treating or caring for a patientundergoing or recovering from a surgical procedure. Pre-operatively, oneof the most common questions asked by patients pertains to the amount ofpain that they will experience following surgery (Vadivelu, N., Yale J.of Biology and Medicine 83 (2010), p. 11-25). Effective analgesia isvital for ensuring patient comfort, encouraging early mobilization,promoting earlier patient discharge from the medical setting (e.g.,hospital, outpatient facility or the like), and for providing enhancedrecovery times. Effective treatment of post-operative pain may alsoreduce the onset/occurrence of chronic pain syndromes such asneuropathic pain and/or the development of depression. Additionaladvantages of effective post-operative pain management include fewerpulmonary and cardiac complications and a reduced risk of deep veinthrombosis (Ramsay, M., Proc (Bayl Univ Med Centr). 2000 July;13(3):244-247). In contrast, inadequate pain control may result inincreased morbidity or mortality (Sharrock N E, et al., Anesth Analg.1995 February; 80(2):242-8).

Unfortunately, although there has been a significant increase inknowledge related to the physiology of pain over the last decade, theresulting implications in clinical practice have failed to follow suit.Even after decades of advances in the understanding of the physiologyand psychology of pain, one of the mainstays of pain therapy remains theuse of opioids. While effective analgesics, opioids also carry with themmany undesirable side effects, such as sedation, respiratory depression,nausea and vomiting, hypotension, bradycardia, risk of addiction, toname a few.

One approach for providing localized, effective, long-acting relief ofpain, particularly acute pain such as post-surgical pain, is theutilization of a sustained or extended release system. Numerous factorscan impact the design of an effective drug delivery system and certainclasses of drugs, such as the local anesthetics, are typicallyconsidered to be relatively short lasting such that they are most oftenused only in relatively minor or moderate procedures. There remains aneed for compositions for the treatment of pain that are long-lasting,efficacious, convenient to administer, and that can overcome some of thedrawbacks associated with the use of opioids. The present compositionsand methods satisfy these and other needs.

BRIEF SUMMARY

In one aspect, a composition comprising an amide-type local anesthetic,a non-steroidal anti-inflammatory drug (NSAID) and a delivery vehicle isprovided.

In one embodiment, the composition is an aqueous based solution.

In another embodiment, the delivery vehicle is a sustained-releasedelivery vehicle.

In one embodiment, the composition is injectable.

In another embodiment, the composition is suitable for administration asan intramuscular injection, transdermally, topically, as a subcutaneousinjection, as a perineural injection or to a wound.

In one embodiment, the sustained-release delivery vehicle is a polymericcomposition, a liposomal composition, a microsphere composition, anon-polymeric composition or an implantable device.

In one embodiment, the sustained release delivery vehicle is not amicrosphere composition.

In one embodiment the sustained release delivery vehicle is not aliposomal composition.

In one embodiment the sustained release delivery vehicle is not anon-polymeric composition.

In one embodiment the sustained release delivery vehicle is not animplantable device.

In one embodiment, the composition has a viscosity of less than 10,000mPa-s when viscosity is measured at 37° C. using a viscometer.

In yet another embodiment, the sustained-release delivery vehicle is aliposome selected from the group consisting of small unilamellarvesicles (SUV), large unilamellar vesicles (LUV), multi-lamellarvesicles (MLV) and multivesicular liposomes (MVL).

In another embodiment, the amide-type local anesthetic is entrapped inan aqueous space of the liposome or in a lipid layer of the liposome.

In another embodiment, the non-steroidal anti-inflammatory drug (NSAID)is entrapped in an aqueous space of the liposome or in a lipid layer ofthe liposome.

In still another embodiment, the sustained-release delivery vehicle is amicrosphere comprised of a bioerodible or biodegradable polymer.

In one embodiment, the amide-type local anesthetic and the non-steroidalanti-inflammatory drug (NSAID) are entrapped in the microsphere.

In one embodiment, the implantable device is an osmotic pump with areservoir comprising the amide-type local anesthetic and thenon-steroidal anti-inflammatory drug (NSAID).

In another embodiment, the sustained-release delivery vehicle is anon-polymeric formulation comprising sucrose acetate isobutyrate.

In still another embodiment, the sustained-release delivery vehicle is apolymeric formulation in the form of a semi-solid polymer formulationcomprising a polymer, the amide-type local anesthetic and thenon-steroidal anti-inflammatory drug (NSAID).

In one embodiment, the polymer is a bioerodible or biodegradablepolymer.

In yet another embodiment, the polymer formulation forms an implant ordepot in situ.

In still another embodiment, the polymer is selected from the groupconsisting of polylactides, polyglycolides, poly(lactic-co-glycolicacid) copolymers, polycaprolactones, poly-3-hydroxybutyrates, andpolyorthoesters.

In a further embodiment, the sustained-release delivery vehicle is apolymeric formulation in the form of a semi-solid polymer formulationcomprising a polyorthoester, the amide-type local anesthetic and thenon-steroidal anti-inflammatory drug (NSAID).

In one embodiment, the amide-type local anesthetic is selected from thegroup consisting of bupivacaine, ropivacaine, levobupivacaine,dibucaine, mepivacaine, procaine, lidocaine, and tetracaine.

In yet another embodiment, the active agent is ropivacaine.

In yet an alternative embodiment, the active agent is bupivacaine.

In a further embodiment related to any one or more of the foregoingembodiments, the non-steroidal anti-inflammatory drug (NSAID) is anenolic-acid NSAID. Exemplary enolic-acid NSAID include meloxicam,piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.

In a specific embodiment, the enolic-acid NSAID is meloxicam.

In a particular embodiment, the composition comprises bupivacaine andmeloxicam.

In one embodiment, the NSAID is not diclofenac.

In another aspect, a composition comprising a delivery vehicle and anamide type local anesthetic of the “caine” classification and anenolic-acid non-steroidal anti-inflammatory drug (NSAID) is provided.

In one embodiment, the amide type local anesthetic is selected from thegroup consisting of bupivacaine and ropivacaine.

In yet another embodiment, the active agent is ropivacaine.

In yet an alternative embodiment, the active agent is bupivacaine.

In a further embodiment related to any one or more of the foregoingembodiments, the non-steroidal anti-inflammatory drug (NSAID) is anenolic-acid NSAID selected from the group consisting of meloxicam,piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.

In a specific embodiment, the enolic-acid NSAID is meloxicam.

In a particular embodiment, the composition comprises bupivacaine andmeloxicam.

In a further embodiment related to any one or more of the foregoingembodiments, the composition is a semi-solid or solid composition.

In one embodiment, the delivery vehicle is a sustained-release deliveryvehicle. In one embodiment, the sustained-release vehicle is a polymericvehicle or formulation.

In another embodiment, the sustained-release polymeric vehicle is asolid or semi-solid vehicle comprising a bioerodible or biodegradablepolymer.

In an embodiment, the biodegradable or bioerodible polymeric formulationcomprises a polymer selected from the group consisting of polylactide,polyglycolide, a poly(lactic-co-glycolic acid) copolymer,polycaprolactone, poly-3-hydroxybutyrate, or a polyorthoester.

In one embodiment, the polyorthoester is selected from thepolyorthoesters represented by Formulas I, II, III and IV set forthherein.

In yet a particular embodiment related to the foregoing, thepolyorthoester is represented by Formula I.

In yet an additional embodiment, the composition or delivery vehiclefurther comprises a solvent. The solvent may be either protic or aproticin nature. In one embodiment, the composition comprises as the deliveryvehicle a polyorthoester and a solvent.

In another embodiment, the sustained-release delivery vehicle isselected from the group consisting of microspheres, microparticles, andhomogeneous or heterogeneous matrix depots. In one embodiment, themicrosphere, microparticle or depot vehicle is biodegradable orbioerodible.

In another embodiment, the sustained-release delivery vehicle is aliposomal formulation or a lipid-based formulation.

In another embodiment, the sustained-release formulation is apolymeric-based solid or semi-solid implant where the amideamide-typelocal anesthetic and the enolic-acid NSAID are dispersed in thepolymeric-based implant. In one embodiment, the implant is a solidpolymeric-based vehicle in the form of a suture or a staple.

In yet an additional aspect, provided is a method for extending thepain-relief profile of a delivery vehicle comprising an amide-type localanesthetic and an efficacy-enhancing amount of an NSAID, to therebyprovide a composition capable of providing effective pain relief for aperiod of time that is extended over that of the same composition absentthe NSAID. In particular, the resulting composition is generallyeffective to provide pain relief from about 1 day to at least about 5days following administration, i.e., is a long-acting formulation forpain relief, rather than a short-acting formulation.

In yet an additional aspect, provided is a method for altering the painrelief profile of a composition comprising a delivery vehicle and anamide-type local anesthetic incorporated and an efficacy-enhancingamount of an enolic acid NSAID in the vehicle, to thereby provide acomposition that exhibits a long-term pain reducing effect over a periodof about 1-5 days, about 1-2 days, about 1-3 days or about 1-4 days, andoptionally beyond, that is at least about 50% of its averagepain-relieving effect exhibited from about 1-5 hourspost-administration.

In a particular embodiment, the composition is effective to providemeasurable plasma concentrations of the amide- or anilide-type localanesthetic and/or the NSAID for a period of at up to about 3 days or upto about 5 days or up to about 7 days or up to about 10 days followingadministration, or for a period of about 1 days to 3 days, about 1 dayto about 5 days, about 1 day to about 7 days, about 3 days to about 5days, about 3 days to about 7 days or about 5 days to about 10 days. Inone embodiment, the plasma concentration of the amide- or anilide-typelocal anesthetic and/or the NSAID is measured by LC/MS/MS (liquidchromatography/tandem mass spectrometry).

In a particular embodiment, the composition is effective to release asignificant portion of both the amide-type local anesthetic and theNSAID from the composition, such that about 80% by weight or more of theamide- or anilide-type local anesthetic and/or the NSAID is released,either in vitro or in vivo, over a period of up to about 3 days or up toabout 5 days or up to about 7 days or up to about 10 days followingadministration or initiation of an in vitro drug release experiment(e.g. as described in Example 5), or for a period of about 1 day toabout 3 days, about 1 day to about 5 days, about 1 day to about 7 daysor about 5 days to about 10 days, about 2 days to about 5 days, about 3days to about 5 days, about 4 days to about 5 days, about 2 days toabout 4 days, about 3 days to about 4 days, or about 3 days, about 4days or about 5 days.

In one embodiment, the composition is a synergistic composition whereinrelease of the amide-type local anesthetic and NSAID in combinationprovides a synergistic level of pain relief that is greater than a levelof pain relief provided by an additive effect of adding the amide-typelocal anesthetic and NSAID independently. In another embodiment, thecomposition provides a duration of pain relief that is longer than aduration resulting from an additive effect of adding the amide-typelocal anesthetic and NSAID independently.

In another aspect, provided is a method of treatment, the methodcomprising dispensing from a needle a composition comprising an amide-or anilide type local anesthetic combined with an NSAID, such as anenolic-acid NSAID, and a delivery vehicle, to thereby achieve acontrolled release of both the local anesthetic and the NSAID from thecomposition, wherein about 80% by weight or more of both drugs arereleased over a period of about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, or about 10days.

In another embodiment, the compositions provided herein are for use in amethod of providing local anesthesia to a patient in need thereof. Thetreatment includes administering to a patient a composition as set forthherein, e.g., comprising an amide or anilide-type local anesthetic, adelivery vehicle and an NSAID, to provide rates of release of both theanesthetic and the NSAID, as well as accompanying pharmacokineticprofiles of each effective for reducing or preventing pain over anextended period following administration. Local administration can be,e.g., at a nerve, into the epidural space, intrathecal, or directly to asurgical site or wound. In one embodiment, about 80% by weight or moreof both drugs are released over a period of about 5 days. In anotherembodiment, the composition is effective to provide significant painrelief for up to about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, or about 7 days following application. In still anotherembodiment, the composition is effective to provide significant painrelief for about 2 hours to about 4 hours, about 2 hours to about 6hours, about 2 hours to about 8 hours, about 2 hours to about 10 hours,about 4 hours to about 12 hours, about 6 hours to about 18 hours, about6 hours to about 24 hours, about 2 hours to about 2 days, about 2 hoursto about 4 days, about 1 hour to about 3 days, about 1 hour to about 5days, about 1 day to about 5 days, about 1 day to about 3 days, about 2days to about 5 days, about 3 days to about 5 days, about 4 days toabout 5 days, about 2 days to about 4 days, about 3 days to about 4days, or about 2 days, about 3 days or about 4 days.

In yet another embodiment, the compositions and delivery systemsprovided herein are effective for reducing or treating acute or chronicpain.

In still another aspect, a method for providing pain relief to a patientin need thereof is provided. The method comprises providing acomposition as described herein, and instructing that the composition beadministered to the patient to provide pain relief for an extendedperiod.

In one embodiment, the extended period of pain relief is at least about5 days. In another embodiment, the extended period is for up to or equalto about 5 days. In still another embodiment, the extended period isfrom about 1 day to at least about 5 days or from about 1 day to up toabout 5 days. In yet another embodiment, the extended period is forabout 3 days.

In one embodiment, the method results in a synergistic increase in painrelief wherein the level of pain relief is greater than a level of painrelief provided by an additive effect of adding the amide-type localanesthetic and NSAID independently. In another embodiment, the methodresults in a synergistic increase in the duration of pain relief whereinthe duration of pain relief is greater than a duration of pain reliefprovided by an additive effect of adding the amide-type local anestheticand NSAID independently.

In one embodiment, the composition is administered as a perineuralinjection. In a further embodiment, the perineural injection is a nerveblock.

In a specific embodiment, the composition is administered as a nerveblock to treat a painful condition in a subject in need thereof.

In a further specific embodiment, the composition is administered as anerve block as prophylactic treatment of a painful condition, such asadministration prior to surgery for the treatment of pain after surgery,in a subject in need thereof.

In another aspect, an aqueous pharmaceutical composition comprising atherapeutically effective amount of meloxicam and a therapeuticallyeffective amount of an amide-type local anesthetic is provided.

In one embodiment, administration of the aqueous pharmaceuticalcomposition to a subject provides pain relief to the subject for aduration of about 1 hour to about 24 hours, about 1 hour to about 16hours, about 1 hour to about 12 hours, about 2 hours to about 12 hours,about 3 hours to about 12 hours, about 4 hours to about 12 hours, about4 hours to about 10 hours, about 5 hours to about 10 hours, about 6hours to about 10 hours, about 6 hours to about 9 hours, about 6 hoursto about 8 hours or about 4 hours to about 8 hours after administrationto the subject. In another embodiment, the duration of analgesia islonger than the duration of pain relief provided by administration of atherapeutically effective amount of an aqueous pharmaceuticalcomposition of the amide-type local anesthetic or the meloxicam alone.

In one embodiment, the amide-type local anesthetic is selected from thegroup consisting of bupivacaine, ropivacaine, levobupivacaine,dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. In anotherembodiment, the amide-type local anesthetic is bupivacaine. In stillanother embodiment, the amide-type local anesthetic is ropivacaine.

In another aspect, a pharmaceutically acceptable aqueous solution ofmeloxicam or pharmaceutically acceptable salt thereof is providedwherein the aqueous solution is suitable for combining with apharmaceutically acceptable aqueous solution of an amide-type localanesthetic to generate a pharmaceutical mixture suitable foradministration to a subject.

In one embodiment, the amide-type local anesthetic is selected from thegroup consisting of bupivacaine, ropivacaine, levobupivacaine,dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. In anotherembodiment, the amide-type local anesthetic is bupivacaine. In stillanother embodiment, the amide-type local anesthetic is ropivacaine.

In one embodiment, the subject is suffering from acute or chronic pain.In another embodiment, the subject is in need of prophylactic treatmentfor pain.

In one embodiment, the pharmaceutical mixture is suitable foradministration as an intramuscular, subcutaneous injection, orperineural injection. In another embodiment, the pharmaceutical mixtureis suitable for intravenous administration. In another embodiment, thepharmaceutical mixture is suitable for administration to a wound.

In another aspect, a method for treating a subject in pain or a subjectin need of prophylactic treatment of pain is provided, wherein themethod comprises administering to the subject an aqueous pharmaceuticalcomposition comprising a therapeutically effective amount of meloxicamand a therapeutically effect amount of an amide-type local anesthetic.

In one embodiment, the amide-type local anesthetic in the aqueouspharmaceutical composition is selected from the group consisting ofbupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine,procaine, lidocaine, and tetracaine. In another embodiment, theamide-type local anesthetic is bupivacaine. In still another embodiment,the amide-type local anesthetic is ropivacaine.

In one embodiment the administration of the aqueous pharmaceuticalcomposition to the subject provides pain relief to the subject for aduration of about 1 hour to about 24 hours, about 2 hours to about 18hours, about 3 hours to about 16 hours, about 4 hours to about 24 hours,about 4 hours to about 22 hours, about 4 hours to about 20 hours, about4 hours to about 18 hours, about 4 hours to about 16 hours, about 4hours to about 14 hours, about 4 hours to about 12 hours, about 6 hoursto about 48 hours, about 6 hours to about 36 hours, about 6 hours toabout 24 hours, about 6 hours to about 20 hours, about 6 hours to about18 hours, about 6 hours to about 16 hours, about 6 hours to about 14hours, about 6 hours to about 12 hours or about 6 hours to about 10hours after administration.

In one embodiment, the pain is chronic or acute pain.

In another aspect, a method for treating a subject in pain or a subjectin need of prophylactic treatment of pain is provided, wherein themethod comprises mixing a pharmaceutical solution of meloxicam or apharmaceutically acceptable salt thereof with a pharmaceutical solutionof amide-type local anesthetic to prepare a mixed solution andadministering the mixed solution to the subject.

In one embodiment the mixed solution is administered to the subjectwithin about 24 hours, about 20 hours, about 16 hours, about 12 hours,about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1hour, about 45 minutes, about 30 minutes, about 15 minutes or about 5minutes after preparing the mixed solution.

In one embodiment, the pharmaceutical solution of meloxicam is anaqueous solution.

In one embodiment, the mixed solution is administered by intramuscular,subcutaneous, or perineural injection. In another embodiment, the mixedsolution is administered to a wound.

In one embodiment the administering of the mixed solution to the subjectprovides pain relief to the subject for a duration of about 1 hour toabout 24 hours, about 2 hours to about 18 hours, about 3 hours to about16 hours, about 4 hours to about 24 hours, about 4 hours to about 22hours, about 4 hours to about 20 hours, about 4 hours to about 18 hours,about 4 hours to about 16 hours, about 4 hours to about 14 hours, about4 hours to about 12 hours, about 6 hours to about 48 hours, about 6hours to about 36 hours, about 6 hours to about 24 hours, about 6 hoursto about 20 hours, about 6 hours to about 18 hours, about 6 hours toabout 16 hours, about 6 hours to about 14 hours, about 6 hours to about12 hours or about 6 hours to about 10 hours after administration.

In another aspect, a delivery system comprised of a polyorthoester, asolvent comprising a triglyceride viscosity reducing agent and a polaraprotic solvent in which the polyorthoester is miscible to form a singlephase, and a therapeutically active agent dispersed or solubilized inthe single phase is provided. In one embodiment, the triglycerideviscosity reducing agent comprises three fatty acid groups eachindependently comprising between 1-7 carbon atoms, which is alsoreferred to herein as a ‘short chain’ triglyceride.

In one embodiment, the active agent is released from the delivery systemover a period ranging from about 1 day to 8 weeks, about 1 day to 7weeks, about 1 day to 6 weeks, about 1 day to 5 weeks, about 1 day to 4weeks, about 1 day to 3 weeks, about 1 day to 2 weeks, about 1 week to 8weeks, about 1 week to 6 weeks, about 1 week to 4 weeks, about 1 day to7 days, about 1 day to 6 days, about 1 day to 5 days, about 1 hour to 24hours, about 2 hours to 18 hours, about 3 hours to 16 hours, about 4hours to 24 hours, about 4 hours to 22 hours, about 4 hours to 20 hours,about 4 hours to 18 hours, about 4 hours to 16 hours, about 4 hours to14 hours, about 4 hours to 12 hours, about 6 hours to 48 hours, about 6hours to 36 hours, about 6 hours to 24 hours, about 6 hours to 20 hours,about 6 hours to 18 hours, about 6 hours to 16 hours, about 6 hours to14 hours, about 6 hours to 12 hours or about 6 hours to 10 hours.

In one embodiment, the delivery system has a viscosity of less thanabout 10,000 mPa-s when viscosity is measured at 25° C. using aviscometer, less than about 5,000 mPa-s when viscosity is measured at25° C. using a viscometer, or less than about 2,500 mPa-s when viscosityis measured at 25° C. using a viscometer. In another embodiment, thedelivery system has a viscosity ranging from about 2500 mPa-s to 10,000mPa-s when measured at 25° C. using a viscometer.

In one embodiment the triglyceride viscosity reducing agent is glycerintriacetate (also called triacetin, 1,2,3-triacetoxypropane, or glyceroltriacetate).

In one embodiment, the polar aprotic solvent is an organic solventhaving a water solubility of greater than 25% by weight of the solventin water at room temperature.

In one embodiment, the polar aprotic solvent has a dipole moment greaterthan about 2 Debye (D).

In one embodiment, the polar aprotic solvent is in a class selected fromthe group consisting of an amide, an ether, a ketone, and a sulfoxide.

In another embodiment, the polar aprotic solvent is a sulfoxide selectedfrom the group consisting of dimethyl sulfoxide anddecylmethylsulfoxide.

In yet another embodiment, the polar aprotic solvent is an amideselected from the group consisting of 2-pyrrolidone, dimethyl formamide,N-methyl-2-pyrrolidone, and dimethyl acetamide.

In one embodiment, the polar aprotic solvent is an ether selected fromdimethyl isosorbide and tetrahydrofuran.

In one embodiment, the polar aprotic solvent is a ketone selected fromthe group consisting of acetone and methyl ethyl ketone.

In one embodiment, the polar aprotic solvent is a lactone selected fromthe group consisting of ester-caprolactone and butyrolactone.

In one embodiment, the polar aprotic solvent is an ester of an alcohol,propylene carbonate (4-methyl-1,3-diololan-2-one).

In one embodiment, the polar aprotic solvent is1-dodecylazacycloheptan-2-one.

In one embodiment, the polar aprotic solvent is dimethylsulfoxide (DMSO)or N-methyl pyrrolidone (NMP) or dimethyl acetamide (DMAC).

In one embodiment, the polar aprotic solvent is dimethylsulfoxide (DMSO)or N-methyl pyrrolidone (NMP).

In one embodiment, the therapeutically active agent is an anti-emetic.

In one embodiment, the therapeutically active agent is granisetron.

In one embodiment, the therapeutically active agent is an anesthetic. Inanother embodiment, the anesthetic is a local amide-type anesthetic. Inyet another embodiment, the anesthetic is selected from the groupconsisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine,procaine, lidocaine, tetracaine, and ropivacaine.

In one embodiment, the therapeutically active agent is ropivacaine orbupivacaine.

In one embodiment, the composition comprising the anesthetic furthercomprises a nonsteroidal anti-inflammatory agent (NSAID). In anotherembodiment, the NSAID is an enolic-acid NSAID. In still anotherembodiment, the NSAID is selected from the group consisting ofmeloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.

In one embodiment, the therapeutically active agent is a opioid. Inanother embodiment, the therapeutically active agent is buprenorphine.

In one embodiment, the polyorthoester is selected from thepolyorthoesters represented by Formulas I, II, III and IV set forthherein below.

In one embodiment, the polyorthoester is the polyorthoester representedby the structure shown as Formula I,

where: R* is a methyl, ethyl, propyl or butyl, n is the number ofrepeating units and is an integer ranging from 5 to 400, and A in eachsubunit is R¹ or R³.

In one embodiment, R* is ethyl.

In one embodiment, A corresponds to R¹, where R¹ is

where p and q are each independently integers ranging from about 1 to20, each R⁵ is independently hydrogen or C₁₋₄ alkyl; and R⁶ is:

where s is an integer from 0 to 10; t is an integer from 2 to 30; and R⁷is hydrogen or C₁₋₄ alkyl. In another embodiment, R7 is C1, C2, C3, orC4 alkyl. In a particular embodiment, R⁷ is H. In still anotherembodiment, the R¹ subunits are α-hydroxy acid-containing subunits. Inanother embodiment, p and q are each independently selected from 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Inyet another embodiment, R5 is independently hydrogen, or C1, C2, C3, orC4 alkyl.

In one embodiment, A corresponds to R³, where R³ is:

and x is an integer ranging from 1 to 100. In another embodiment, x isselected from 0, 1, 2, 3, 4, and 5; y is an integer in a range from 2 to30; and R⁸ is hydrogen or C₁₋₄ alkyl. In still another embodiment, R⁸ isa C1, C2, C3 or C4 alkyl. In another embodiment, R⁸ is H.

In one embodiment, the polyorthoester is one in which A is R¹ or R³,where R¹ is

where p and q are each independently selected from 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 in any repeatingunit, where the average number of p or the average number of the sum ofp and q (p+q) is between about 1 and 7; x and s are each independentlyan integer ranging from 0 to 10; and t and y are each independently aninteger ranging from 2 to 30. In another embodiment, the sum of p and qis 1, 2, 3, 4, 5, 6 or 7 in any repeating unit of R¹. In yet anotherembodiment, R⁵ is H.

In one embodiment, A is R¹ or R³, where R¹ is

and p and q are each independently integers ranging from about 1 and 20,about 1 and 15, or about 1 and 10 in any repeating unit of R¹, where theaverage number of p or the average number of the sum of p and q (i.e.,p+q) is between about 1 and 7. In another embodiment, x and s eachindependently range from 0 to about 7 or from 1 to about 5. In stillanother embodiment, t and y each independently range from 2 to 10.

In one embodiment, R⁵ is hydrogen or methyl.

In one embodiment, s and x are each independently selected from 1, 2, 3,4, 5, 6, 7 and 8. In another embodiment, s is 2. In still anotherembodiment, x is 2.

In one embodiment, the polyorthoester comprises alternating residues of3,9-diethyl-3,9-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl and A:

where A is as described above.

In one particular embodiment related to the polyorthoester in thedelivery system, the polyorthoester has a molecular weight ranging fromabout 2,500 daltons to 10,000 daltons.

In one embodiment related to the delivery system, the polyorthoester isrepresented by the structure shown as Formula I and is in an amountranging from about 65 to 75 percent by weight of the delivery system.

In one embodiment related to the delivery system, the triglycerideviscosity reducing agent is present in an amount ranging from about 10wt % to 50 wt %, 10 wt % to 35 wt %, 15 wt % to 30 wt %, or 20 wt % to25 wt %, or about 15 wt %, 16 wt %, 17 wt %, 18 wt %, 19 wt %, 20 wt %,21 wt %, 22 wt %, 23 wt %, 24 wt %, 25 wt %, 27 wt %, 28 wt %, 29 wt %,30 wt %, 31 wt %, 32 wt %, 33 wt %, 34 wt %, or 35 wt % of the deliverysystem.

In one embodiment related to the delivery system, the aprotic solvent ispresent in an amount ranging from about 10 wt % to 35 wt %, 10 wt % to30 wt %, 10 wt % to 20 wt %, 10 wt % to 15 wt %, or about 2 wt %, 3 wt%, 4 wt %, 5 wt %, 6 wt %, 7 wt %, 8 wt %, 9 wt %, 10 wt %, 11 wt %, 12wt %, 13 wt %, 14 wt %, 15 wt %, 16 wt %, 17 wt %, 18 wt %, 19 wt %, or20 wt % of the delivery system.

In one embodiment related to the delivery system, the active agent ispresent in an amount ranging from about 1 to 8 percent, 2 to 6 percent,2 to 5 percent, or 1 to 5 percent by weight of the delivery system.

In one embodiment related to the delivery system, the polyorthoester isrepresented by the structure shown as Formula I in accordance with anyone or more of the combinations and sets of variables related thereto asprovided herein, the active agent is granisetron in an amount rangingfrom about 1 to 5 percent by weight of the delivery system, the aproticsolvent is DMSO or NMP in an amount ranging from about 5 to 35 percentby weight of the delivery system, and the triglyceride viscosityreducing agent is triacetin in an amount ranging from about 10 to 30percent by weight of the delivery system.

In a particular embodiment, the solvent comprising the triglycerideviscosity reducing agent and the polar aprotic solvent is in an amountranging from about 15 to 50 percent by weight of the delivery system,and the therapeutic agent is in an amount ranging from about 3 to 30percent by weight of the delivery system.

In yet another embodiment, the polyorthoester is represented by thestructure shown as Formula I in accordance with any one or more of thecombinations and sets of variables related thereto as provided herein,the active agent is ropivacaine or bupivacaine in an amount ranging fromabout 3 to 30 percent by weight of the delivery system, the triglycerideviscosity reducing agent is triacetin in an amount ranging from about 15to 30 percent by weight of the delivery system, and the solvent isselected from dimethyl sulfoxide, dimethyl acetamide and N-methylpyrrolidone and is in an amount ranging from about 15 to 50 percent byweight of the delivery system.

In one embodiment, the polyorthoester is represented by the structureshown as Formula I, the active agent is granisetron in an amount rangingfrom about 1 to 5 percent by weight of the composition, and the solventis DMSO in an amount ranging from about 10 to 35 percent by weight ofthe composition.

In another aspect, a method of administering a therapeutically activeagent is provided. The method comprises dispensing from a needle adelivery system or a composition as described herein comprising apolyorthoester, a triglyceride viscosity reducing agent and an aproticsolvent in which the polyorthoester is miscible to form a single phase,and a therapeutically active agent dispersed or solubilized in thesingle phase, wherein the solvent is selected to achieve a controlledrelease of the active agent from the composition according to apredetermined release profile, and wherein the active agent is releasedfrom the delivery system or composition over a period ranging from about1 day to 8 weeks, 1 day to 7 weeks, 1 day to 6 weeks, 1 day to 5 weeks,1 day to 4 weeks, 1 day to 3 weeks, 1 day to 2 weeks, 1 week to 8 weeks,1 week to 6 weeks, 1 week to 4 weeks, 1 day to 7 days, 1 day to 6 days,1 day to 5 days, 1 hour to 24 hours, 2 hours to 18 hours, 3 hours to 16hours, 4 hours to 24 hours, 4 hours to 22 hours, 4 hours to 20 hours, 4hours to 18 hours, 4 hours to 16 hours, 4 hours to 14 hours, 4 hours to12 hours, 6 hours to 48 hours, 6 hours to 36 hours, 6 hours to 24 hours,6 hours to 20 hours, 6 hours to 18 hours, 6 hours to 16 hours, 6 hoursto 14 hours, 6 hours to 12 hours or 6 hours to 10 hours.

In another aspect, provided is a method of treatment comprisingdispensing from a needle to a patient in need there of a delivery systemcomposition comprised of a polyorthoester, comprising a triglycerideviscosity reducing agent, an aprotic solvent in which the polyorthoesteris miscible to form a single phase, and a therapeutically active agentdispersed or solubilized in the single phase, wherein the triglycerideviscosity reducing agent and the aprotic solvent are selected to achievea controlled release of the active agent from the composition accordingto a predetermined release profile, and wherein the active agent isreleased from the delivery system or composition over a period rangingfrom about 1 day to 8 weeks, 1 day to 7 weeks, 1 day to 6 weeks, 1 dayto 5 weeks, 1 day to 4 weeks, 1 day to 3 weeks, 1 day to 2 weeks, 1 weekto 8 weeks, 1 week to 6 weeks, 1 week to 4 weeks, 1 day to 7 days, 1 dayto 6 days, 1 day to 5 days, 1 hour to 24 hours, 2 hours to 18 hours, 3hours to 16 hours, 4 hours to 24 hours, 4 hours to 22 hours, 4 hours to20 hours, 4 hours to 18 hours, 4 hours to 16 hours, 4 hours to 14 hours,4 hours to 12 hours, 6 hours to 48 hours, 6 hours to 36 hours, 6 hoursto 24 hours, 6 hours to 20 hours, 6 hours to 18 hours, 6 hours to 16hours, 6 hours to 14 hours, 6 hours to 12 hours or 6 hours to 10 hours.In one embodiment, the delivery system is administered as a perineuralinjection. In a further embodiment, the perineural injection is a nerveblock.

In a specific embodiment, the delivery system is administered as a nerveblock to treat a painful condition in a subject in need thereof.

In a further specific embodiment, the delivery system is administered asa nerve block as prophylactic treatment of a painful condition, such asadministration prior to surgery for the treatment of pain after surgery,in a subject in need thereof.

For each of the above embodiments of the composition, or related methodsor systems, each embodiment directed to an amide- or anilide-type localanesthetic is meant to apply to each and every embodiment of the NSAID,and each embodiment of delivery vehicle is meant to apply to eachembodiment of the combination of the amide- or anilide-type localanesthetic and the enolic-acid NSAID, etc.

Additional embodiments of the present systems, compositions and methodswill be apparent from the following description, drawings, examples, andclaims. As can be appreciated from the foregoing and followingdescription, each and every feature described herein, and each and everycombination of two or more of such features, is included within thescope of the present disclosure provided that the features included insuch a combination are not mutually inconsistent. In addition, anyfeature or combination of features may be specifically excluded from anyembodiment of the present invention. Additional aspects and advantagesof the present invention are set forth in the following description andclaims, particularly when considered in conjunction with theaccompanying examples and drawings.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1B are graphs of plasma concentration of bupivacaine (FIG. 1A)and of meloxicam (FIG. 1B), in ng/mL, as a function of time, in hours,after administration in vivo to sheep of exemplary compositionscomprised of a polyorthoester delivery vehicle and bupivacaine andmeloxicam at concentrations of 15 wt % bupivacaine/3 wt % meloxicam(closed squares; composition no. 8026-04-03); 10 wt % bupivacaine/0.75wt % meloxicam (open circles; composition no. 8026-04-04); and 5 wt %bupivacaine/0.38 wt % meloxicam (open triangles; composition no.8026-04-05);

FIGS. 2A-2B are graphs of plasma concentration of bupivacaine (FIG. 2A)and of meloxicam (FIG. 2B), in ng/mL, as a function of time, in hours,after administration in vivo to a dog of a composition (no. 8026-04-07)comprised of a polyorthoester delivery vehicle and 5 wt % bupivacaineand 0.15 wt % meloxicam;

FIG. 3 is a bar graph of withdrawal force, in gram force, as a functionof time, in hours and days, after administration in vivo to pigs ofcompositions comprised of a polyorthoester delivery vehicle and either(i) 15 wt % bupivacaine administered by injection (vertical dashes fill)or by instillation (vertical line fill) or (ii) 5 wt % ropivacaineadministered by injection (horizontal line fill) or instillation(diamond crosshatch fill), and bars with dotted fill represent theresponse for the control group treated with saline;

FIG. 4 is a bar graph of withdrawal force, in gram force, as a functionof time, in hours and days, after administration by subcutaneousinjection to a wound incision in vivo in pigs of compositions comprisedof a polyorthoester delivery vehicle and (i) 5 wt % ropivacaine with0.6% maleic acid (horizontal line fill), (ii) 5 wt % ropivacaine with0.2% maleic acid (diamond crosshatch fill), (iii) 15 wt % bupivacaineand 7.5 wt % diclofenac (vertical dashes fill), or (iv) 15 wt %bupivacaine and 3.5 wt % meloxicam (vertical line fill); bars withdotted fill represent the response for the control group treated withsaline;

FIGS. 5A-5B are bar graphs of withdrawal force, in gram force, as afunction of time, in hours and days, after administration bysubcutaneous injection to a wound incision in vivo in pigs ofcompositions comprised of a polyorthoester delivery vehicle and 5 wt %bupivacaine in combination with meloxicam at 0.08 wt % (vertical dashfill), 0.19 wt % meloxicam (vertical line fill), and 0.3 wt % meloxicam(horizontal line fill), a composition comprised of a polyorthoesterdelivery vehicle and 0.15 wt % meloxicam alone (dotted fill) (FIG. 5A)and compositions comprised of a polyorthoester delivery vehicle and 5 wt% ropivacaine in combination with 0.38 wt % meloxicam (diamondcrosshatch fill) or with 5 wt % ropivacaine alone (no fill; open bars)(FIG. 5B);

FIGS. 6A-6B are graphs of plasma concentration of bupivacaine (FIG. 6A)and of meloxicam (FIG. 6B), in ng/mL, as a function of time, in hours,after administration in vivo of exemplary compositions comprised of apolyorthoester delivery vehicle comprising triacetin (open circles) orno triacetin (triangles) with bupivacaine and meloxicam;

FIGS. 7A-7B are graphs of plasma concentration of bupivacaine (FIG. 7A)and of meloxicam (FIG. 7B), in ng/mL, as a function of time, in hours,after administration in vivo to dogs of exemplary compositions comprisedof bupivacaine and meloxicam in a polyorthoester delivery vehiclecomprising 30 wt % triacetin (open circles, composition no. 8026-10-05)or 35 wt % triacetin (triangles, composition no. 8026-10-03);

FIG. 8 is a bar graph of withdrawal force, in gram force, as a functionof time, in hours and days, after administration in vivo to pigs ofcompositions comprised of a polyorthoester delivery vehicle, 2.5 wt %bupivacaine alone (Group 4, 8026-13-01, vertical dashes fill) or 2.5 wt% bupivacaine, 0.0175 wt % meloxicam and 0.15% maleic acid (Group 3,8026-10-01, vertical line fill) or 0.10 wt % maleic acid (Group 5,8026-0-02, horizontal line fill), or a buffered solution of 0.5 wt %bupivacaine (no fill; open bars, Group 2); bars with dotted fillrepresent the response for the control group treated with saline.

DETAILED DESCRIPTION I. Definitions

As used in this specification, the singular forms “a,” “an,” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to a “polymer” includes a single polymer aswell as two or more of the same or different polymers, reference to an“excipient” includes a single excipient as well as two or more of thesame or different excipients, and the like.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 10 to 20weight percent (wt %) is stated, it is intended that 11, 12, 13, 14, 15,16, 17, 18, and 19 wt % are also explicitly disclosed, as well as therange of values greater than or equal to 10 wt % up to about 20 wt % andthe range of values less than or equal to 20 wt % down to about 10 wt %.

“Bioerodible”, “bioerodibility” and “biodegradable”, which are usedinterchangeably herein, refer to the degradation, disassembly ordigestion of a polymer by action of a biological environment, includingthe action of living organisms and most notably at physiological pH andtemperature. As an example, a principal mechanism for bioerosion of apolyorthoester is hydrolysis of linkages between and within the units ofthe polyorthoester.

A “polymer susceptible to hydrolysis” such as a polyorthoester refers toa polymer that is capable of degradation, disassembly or digestion viareaction with water molecules. Such a polymer contains hydrolyzablegroups in the polymer. Examples of polymers susceptible to hydrolysismay include, but are not limited to, polymers described herein, andthose described in U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648,4,138,344, 4,180,646, 4,304,767, 4,957,998, 4,946,931, 5,968,543,6,613,335, and 8,252,304, and U.S. Patent Publication No. 2007/0265329,which are incorporated herein by reference in its entirety.

“Molecular mass” in the context of a polymer such as a polyorthoester,refers to the nominal average molecular mass of a polymer, typicallydetermined by size exclusion chromatography, light scatteringtechniques, or velocity. Molecular weight can be expressed as either anumber-average molecular weight or a weight-average molecular weight.Unless otherwise indicated, all references to molecular weight hereinrefer to the weight-average molecular weight. Both molecular weightdeterminations, number-average and weight-average, can be measured usinggel permeation chromatographic or other liquid chromatographictechniques. Other methods for measuring molecular weight values can alsobe used, such as the measurement of colligative properties (e.g.,freezing-point depression, boiling-point elevation, or osmotic pressure)to determine number-average molecular weight or the use of lightscattering techniques, ultracentrifugation or viscometry to determineweight-average molecular weight. The polymers of the invention aretypically polydisperse (i.e., number-average molecular weight andweight-average molecular weight of the polymers are not equal),possessing low polydispersity values such as less than about 3.0, lessthan about 2.75, less than about 2.25, less than about 1.5, and lessthan about 1.03.

“Semi-solid” denotes the mechano-physical state of a material that isflowable under moderate stress. More specifically, a semi-solid materialwill generally have a viscosity between about 1,000 and 3,000,000 mPa-sat 37° C., especially between about 1,000 and 50,000 mPa-s at 37° C.

An “active agent” or “active ingredient” refers to any compound ormixture of compounds which produces a beneficial or useful result.Generally, “active agent” or “drug” refers to any organic or inorganiccompound or substance having bioactivity and adapted or used fortherapeutic purposes. As used herein, reference to a drug, as well asreference to other chemical compounds herein, is meant to include thecompound in any of its pharmaceutically acceptable forms, includingisomers such as diastereomers and enantiomers, salts, solvates, andpolymorphs, particular crystalline forms, as well as racemic mixturesand pure isomers of the compounds described herein, where applicable.Active agents are distinguishable from such components as vehicles,carriers, diluents, lubricants, binders and other formulating aids, andencapsulating or otherwise protective components. Examples of activeagents are pharmaceutical, agricultural or cosmetic agents.

Examples of active agents are pharmaceutical, agricultural or cosmeticagents. Suitable pharmaceutical agents include locally or systemicallyacting pharmaceutically active agents which may be administered to asubject by topical or intralesional application (including, for example,applying to abraded skin, lacerations, puncture wounds, etc., as well asinto surgical wounds or incisions) or by injection, such assubcutaneous, intradermal, intramuscular, intraocular or intra-articularinjection. Suitable pharmaceutical agents include polysaccharides, DNAand other polynucleotides, antisense oligonucleotides, antigens,antibodies, vaccines, vitamins, enzymes, proteins, naturally occurringor bioengineered substances, and the like, anti-infectives (includingantibiotics, antivirals, fungicides, scabicides or pediculicides),antiseptics (e.g., benzalkonium chloride, benzethonium chloride,chlorhexidine gluconate, mafenide acetate, methylbenzethonium chloride,nitrofurazone, nitromersol and the like), steroids (e.g., estrogens,progestins, androgens, adrenocorticoids and the like), opioids (e.g.buprenorphine, butorphanol, dezocine, meptazinol, nalbuphine,oxymorphone and pentazocine), therapeutic polypeptides (e.g. insulin,erythropoietin, morphogenic proteins such as bone morphogenic protein,and the like), analgesics and anti-inflammatory agents (e.g., aspirin,ibuprofen, naproxen, ketorolac, COX-1 inhibitors, COX-2 inhibitors andthe like), antipsychotic agents (for example, phenothiazines includingchlorpromazine, triflupromazine, mesoridazine, piperacetazine andthioridazine; thioxanthenes including chlorprothixene and the like),antiangiogenic agents (e.g., combresiatin, contortrostatin, anti-VEGFand the like), anti-anxiety agents (for example, benzodiazepinesincluding diazepam, alprazolam, clonazepam, oxazepam; and barbiturates),antidepressants (including tricyclic antidepressants and monoamineoxidase inhibitors including imipramine, amitriptyline, doxepin,nortriptyline, amoxapine, tranylcypromine, phenelzine and the like),stimulants (for example, methylphenidate, doxapram, nikethamide and thelike), narcotics (for example, buprenorphine, morphine, meperidine,codeine and the like), analgesic-antipyretics and anti-inflammatoryagents (for example, aspirin, ibuprofen, naproxen and the like), localanesthetics (e.g., the amide- or anilide-type local anesthetics such asbupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine,lidocaine, tetracaine, ropivacaine, and the like), fertility controlagents, chemotherapeutic and anti-neoplastic agents (for example,mechlorethamine, cyclophosphamide, 5-fluorouracil, thioguanine,carmustine, lomustine, melphalan, chlorambucil, streptozocin,methotrexate, vincristine, bleomycin, vinblastine, vindesine,dactinomycin, daunorubicin, doxorubicin, tamoxifen and the like),cardiovascular and anti-hypertensive agents (for example, procainamide,amyl nitrite, nitroglycerin, propranolol, metoprolol, prazosin,phentolamine, trimethaphan, captopril, enalapril and the like), drugsfor the therapy of pulmonary disorders, anti-epilepsy agents (forexample, phenyloin, ethotoin and the like), anti-hidrotics,keratoplastic agents, pigmentation agents or emollients, antiemeticagents (such as ondansetron, granisetron, tropisetron, metoclopramide,domperidone, scopolamine, palonosetron, and the like). The compositionof the present application may also be applied to other locally actingactive agents, such as astringents, antiperspirants, irritants,rubefacients, vesicants, sclerosing agents, caustics, escharotics,keratolytic agents, sunscreens and a variety of dermatologics includinghypopigmenting and antipruritic agents. The term “active agents” furtherincludes biocides such as fungicides, pesticides and herbicides, plantgrowth promoters or inhibitors, preservatives, disinfectants, airpurifiers and nutrients. Pro-drugs and pharmaceutically acceptable saltsof the active agents are included within the scope of the presentapplication.

A “small molecule” is a molecule, typically a drug, having a molecularweight of less than about 900 daltons.

The term “amide-type” as used herein refers to an amide- oramino-anilide-type or “-caine” class of local anestheticamide, such asbupivacaine, levobupivacaine, ropivacaine, etidocaine, lidocaine,mepivacaine, prilocaine and the like. Molecules in this class contain anamino functionality as well as an anilide group, for example, an amidegroup formed from the amino nitrogen of a phenyl-substituted aniline.These molecules are generally weak bases, with pKb values ranging fromabout 5.8 to about 6.4.

An “enolic-acid NSAID” as used herein refers to non-steroidalanti-inflammatory drug of the Oxicam class such as meloxicam, piroxicam,tenoxicam, droxicam (prodrug of piroxicam), lornoxicam and the like.Molecules in this class contain an acidic enol functional group.

“Pharmaceutically acceptable salt” denotes a salt form of a drug havingat least one group suitable for salt formation that causes nosignificant adverse toxicological effects to the patient.Pharmaceutically acceptable salts include salts prepared by reactionwith an inorganic acid, an organic acid, a basic amino acid, or anacidic amino acid, depending upon the nature of the functional group(s)in the drug. Suitable pharmaceutically acceptable salts include acidaddition salts which may, for example, be formed by mixing a solution ofa basic drug with a solution of an acid capable of forming apharmaceutically acceptable salt form of the basic drug, such ashydrochloric acid, iodic acid, fumaric acid, maleic acid, succinic acid,acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid,sulfuric acid and the like. Typical anions for basic drugs, when inprotonated form, include chloride, sulfate, bromide, mesylate, maleate,citrate and phosphate. Suitable pharmaceutically acceptable salt formsare found in, e.g., Handbook of Pharmaceutical Salts: Properties,Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002; P. H. Stahl andC. G. Wermuth, Eds.

As referred to herein, an “organic acid” is an organic molecule havingat least one carboxylic acid group that generally possesses a molecularweight that is less than about 300 daltons. An organic acid may have 2or more carboxylic acid groups, e.g., 2, 3, or 4, carboxylic acidgroups. The organic acid may be aliphatic or aromatic, and mayoptionally contain additional non-basic substituents such as hydroxyl,ester, or the like. Aliphatic organic acids may also contain one or moreelements of unsaturation, e.g., a double or a triple bond. Exemplaryorganic acids include ethanoic acid, propanoic acid, butanoic acid,pentanoic acid, benzoic acid, acetyl salicylic acid, citric acid,fumaric acid, maleic acid, salicylic acid, succinic acid, oxalic acid,malonic acid, glutaric acid, adipic acid, pimelic acid, and so forth.

“Polyorthoester-compatible” refers to, in one particular aspect of theproperties of the polyorthoester, the properties of an excipient which,when mixed with the polyorthoester, forms a single phase and does notcause any chemical changes to the polyorthoester.

A “therapeutically effective amount” means the amount that, whenadministered to a human or an animal for treatment of a disease, issufficient to effect treatment for that disease or condition.

“Treating” or “treatment” of a disease or condition includes preventingthe disease or condition from occurring in a human or an animal that maybe predisposed to the disease or condition but does not yet experienceor exhibit symptoms of the disease or condition (prophylactictreatment), inhibiting the disease or condition (slowing or arrestingits development), providing relief from the symptoms or side-effects ofthe disease or condition (including palliative treatment), and relievingthe disease or condition (causing regression of the disease).

As used herein, “synergistic” when used in relation to the combinationrefers to a combination that allows a lower amount of analgesic agent(amide-type local anesthetic) and, in some embodiments, also a loweramount of NSAID, than would be required to achieve a given level ofanalgesia or pain relief if the amide-type local anesthetic or NSAIDwere administered alone. The synergistic combination may allow a loweramount of amide-type local anesthetic and NSAID to be administered in asingle dose to provide a given level of analgesia or pain relief than ifthe amide-type local anesthetic or NSAID were administered alone therebyproviding a greater than additive analgesic effect in combination. Insome instances, the lower amount of the amide or anilide-type localanesthetic and NSAID is a sub-analgesic amount in which one or both ofthe components of the combination are administered at a dosage normallyconsidered not to provide an analgesic or pain relief effect.

Alternatively, the term “synergistic” when used in relation to thecombination refers to a combination that extends the duration or degreeof the analgesic or pain relief effect beyond the duration observed wheneither the amide-type local anesthetic or the NSAID is administeredalone. In this instance, the amount of amide-type local anestheticand/or the NSAID may be the same as the amount normally provided in asingle dose to achieve analgesia, thereby allowing a lower amount ofamide or anilide-type local anesthetic and NSAID to be administered overthe course of multiple doses of analgesic or pain relief therapy asdosing is less frequent a allowing greater analgesia or pain relief thanwould otherwise be achievable with a given dose of amide-type localanesthetic or NSAID.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.

The term “substantially” in reference to a certain feature or entitymeans to a significant degree or nearly completely (i.e. to a degree of85% or greater) in reference to the feature or entity.

The term “about,” particularly in reference to a given quantity, ismeant to encompass deviations of plus or minus 5%, 10%, 15% or 20%.

Additional definitions may also be found in the sections which follow.

II. Compositions and Methods of Use

Currently available local anesthetic formulations used to managepost-operative pain generally don't work particularly well after 24hours—i.e., they are short acting in nature. In exploring the use ofsemi-solid compositions of amide-type anesthetics such as bupivacaine orropivacaine (in free base form) with a model delivery vehicle in theform of a polyorthoester as a local anesthetic for treatingpost-operative pain, it was observed that some of the compositions,while effective immediately after application to the surgical site (fora period of up to about 5 hours post-application or even over the first24 hours or so), diminished in their efficacy when considered in thedays following surgery. More specifically, compositions comprisingbupivacaine or ropivacaine as the only active agent in a deliveryvehicle generally resulted in significantly diminished efficacy over theperiod from about 1-3 days post-surgery, when compared to their efficacyin the short-term (e.g., from about 1-5 hours or so followingapplication) (see FIG. 3). However plasma concentrations of thecorresponding compositions containing only bupivacaine or ropivacainedemonstrate a relatively constant plasma concentration over the sameperiod indicating drug release is relatively constant (see FIG. 1A).While exploring ways in which to provide more effective, long-actingcompositions comprised of an amide local anesthetic, the Applicantsdiscovered that the incorporation of an NSAID into the composition,e.g., an enolic-acid NSAID, was extremely effective in altering thepharmacodynamics of the resulting compositions. While a small drop inefficacy was still observed for the resulting composition from about 5hours to 24 hours post-application (see FIG. 4 and FIGS. 4 and 5A-5B),interestingly, the efficacy of the composition increased beyond theefficacy achieved with compositions comprised of amide-type localanesthetic as the sole active agent such that pain relief (i.e.,efficacy) during the period from about 1 day or about 2 days to up toabout 5 or 6 days following administration, and optionally longer, wassimilar to that provided in the first 5 hours post-administration. Whilethis surprising and advantageous effect was observed for compositionscomprising meloxicam, a similar recovery of efficacy was not observedfor composition comprising the same amide-type local anesthetic and 7.5wt % of a different chemical class of NSAID, the heteroaryl acetic acid,diclofenac (see FIG. 4). Moreover, the degree of efficacy restored andprovided by the composition composed of amide-type local anesthetic andenolic-acid NSAID in a delivery vehicle from about 2 days to at leastabout 5 days following administration was greater than the resultexpected by the mere addition of the enolic-acid NSAID to theformulation; that is, the amide-type local anesthetic and theenolic-acid NSAID act synergistically rather than additively. See, e.g.,the results provided in FIG. 4 discussed below.

Thus, in one embodiment, the Applicants have discovered that theaddition of an enolic-acid NSAID to compositions comprising an amidetype local anesthetic and a delivery vehicle is effective to (i) modifya short-acting, anesthetic formulation into one effective to providelong-lasting pain relief, over a period of at least about 3-5 days, (ii)provide a degree of pain relief that is greater than expected, basedupon the mere additive effect of the drugs, i.e., a synergistic effect,and (iii) provide measurable plasma concentrations of both theamide-type local anesthetic and the NSAID for a period of at least about5 days following administration, among having other beneficial features.

Accordingly, the systems and compositions described herein generallycomprise an amide-type local anesthetic, an enolic-acid NSAID and adelivery vehicle. The long-acting compositions and systems find use, forexample, as drug delivery systems or as medical or surgical devices,e.g., for treatment of pain, such as post-operative pain. Thecomposition components are described below, e.g., in Examples 1-8.

In another embodiment, Applicants have discovered that use of atriglyceride solvent in compositions comprising a polyorthoesterdelivery vehicle and an active agent provides a substantial reduction inviscosity of the composition, relative to a similar composition absentthe triglyceride solvent, without altering the release kinetics of theactive agent(s) from the composition or altering the pharmokineticprofile of the active agent(s), relative to that of a composition absentthe triglyceride solvent. The reduced viscosity of the compositionsoffers significant clinical advantages in terms of ease ofadministration via needle delivery at room temperature. Exemplarycompositions demonstrating these unexpected findings are describedbelow, e.g, in Examples 9-15.

1. Compositions for Analgesia

In one aspect, compositions comprising an amide-type local anesthetic,an enolic-acid non-steroidal anti-inflammatory drug (NSAID) and adelivery vehicle are provided. In this section, each of the compositioncomponents is described.

Amide-Type Local Anesthetic

The composition comprises a local anesthetic of the amide type. Localanesthetics belonging to this class include bupivacaine,levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine,tetracaine, ropivacaine, and the like. These compounds arealkaline-amides possessing pKb values ranging from 5.8 to 6.4. That is,the drugs contain protonizable tertiary amine functions. For example,the pKa values of ropivacaine, lidocaine, and bupivacaine are 8.1, 7.7and 8.1, respectively. The amide-type drugs are provided in thecompositions either in their neutral, base form or as theircorresponding acid-addition salts, or as a mixture of both forms.

In one embodiment, the amide type local anesthetic is added to thecomposition in its free base form. The amide-type anesthetic may beprovided as a racemic mixture, i.e., containing equal amounts of the Rand S enantiomers, or may be provided as a single enantiomer, or may beprovided as an unequal mixture of enantiomers in which one enantiomer isin excess.

In one particular embodiment, the composition comprises bupivacaine asthe local anesthetic. In a further embodiment, the composition comprisesas the active agent ropivacaine.

In yet one or more additional embodiments, the composition comprises anyone or more of the amide-type local anesthetics described above such as,for example, levobupivacaine, dibucaine, mepivacaine, procaine,lidocaine, tetracaine, and the like. In still another embodiment, theamide-type local anesthetic is selected from the group consisting ofbupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine,procaine, lidocaine, and tetracaine.

The composition may also comprise in addition to the amide-type localanesthetic and the enolic acid NSAID (described below), one or moreadditional bioactive agents.

The amide-type local anesthetic is dissolved or dispersed into thecomposition as provided herein. The concentration of the amide-typelocal anesthetic in the composition may vary from about 1 wt % to 30 wt%, 1 wt % to 10 wt %, 10 wt % to 20 wt %, 2 wt % to 5 wt %, 10 wt % to15 wt %, or 15 wt % to 20 wt % and may be 1 wt %, 1.1 wt %, 1.2 wt %,1.3 wt %, 1.4 wt %, 1.5 wt %, 1.6 wt %, 1.7 wt %, 1.8 wt %, 1.9 wt %, 2wt %, 2.1 wt %, 2.2 wt %, 2.3 wt %, 2.4 wt %, 2.5 wt %, 2.6 wt %, 2.7 wt%, 2.8 wt %, 2.9 wt %, 3 wt %, 3.1 wt %, 3.2 wt %, 3.3 wt %, 3.4 wt %,3.5 wt %, 3.6 wt %, 3.7 wt %, 3.8 wt %, 3.9 wt %, 4 wt %, 4.1 wt %, 4.2wt %, 4.3 wt %, 4.4 wt %, 4.5 wt %, 4.6 wt %, 4.7 wt %, 4.8 wt %, 4.9 wt%, 5 wt %, 5 wt %, 5.1 wt %, 5.2 wt %, 5.3 wt %, 5.4 wt %, 5.5 wt %, 5.6wt %, 5.7 wt %, 5.8 wt %, 5.9 wt %, 6 wt %, 6.1 wt %, 6.2 wt %, 6.3 wt%, 6.4 wt %, 6.5 wt %, 6.6 wt %, 6.7 wt %, 6.8 wt %, 6.9 wt %, 7 wt %,7.1 wt %, 7.2 wt %, 7.3 wt %, 7.4 wt %, 7.5 wt %, 7.6 wt %, 7.7 wt %,7.8 wt %, 7.9 wt %, 8 wt %, 8.1 wt %, 8.2 wt %, 8.3 wt %, 8.4 wt %, 8.5wt %, 8.6 wt %, 8.7 wt %, 8.8 wt %, 8.9 wt %, 9 wt %, 9.1 wt %, 9.2 wt%, 9.3 wt %, 9.4 wt %, 9.5 wt %, 9.6 wt %, 9.7 wt %, 9.8 wt %, 9.9 wt %,10 wt %, 11 wt %, 11.1 wt %, 11.2 wt %, 11.3 wt %, 11.4 wt %, 11.5 wt %,11.6 wt %, 11.7 wt %, 11.8 wt %, 11.9 wt %, 12 wt %, 12.1 wt %, 12.2 wt%, 12.3 wt %, 12.4 wt %, 12.5 wt %, 12.6 wt %, 12.7 wt %, 12.8 wt %,12.9 wt %, 13 wt %, 13.1 wt %, 13.2 wt %, 13.3 wt %, 13.4 wt %, 13.5 wt%, 13.6 wt %, 13.7 wt %, 13.8 wt %, 13.9 wt %, 14 wt %, 14.1 wt %, 14.2wt %, 14.3 wt %, 14.4 wt %, 14.5 wt %, 14.6 wt %, 14.7 wt %, 14.8 wt %,14.9 wt %, 15 wt %, 15 wt %, 15.1 wt %, 15.2 wt %, 15.3 wt %, 15.4 wt %,5.5 wt %, 15.6 wt %, 15.7 wt %, 15.8 wt %, 15.9 wt %, 16 wt %, 16.1 wt%, 16.2 wt %, 16.3 wt %, 16.4 wt %, 16.5 wt %, 16.6 wt %, 16.7 wt %,16.8 wt %, 16.9 wt %, 17 wt %, 17.1 wt %, 17.2 wt %, 17.3 wt %, 17.4 wt%, 17.5 wt %, 17.6 wt %, 17.7 wt %, 17.8 wt %, 17.9 wt %, 18 wt %, 18.1wt %, 18.2 wt %, 18.3 wt %, 18.4 wt %, 18.5 wt %, 18.6 wt %, 18.7 wt %,18.8 wt %, 18.9 wt %, 19 wt %, 19.1 wt %, 19.2 wt %, 19.3 wt %, 19.4 wt%, 19.5 wt %, 19.6 wt %, 19.7 wt %, 19.8 wt %, 19.9 wt %, 20 wt %, 21 wt%, 22 wt %, 23 wt %, 24 wt %, 25 wt %, 26 wt %, 27 wt %, 28 wt %, 29 wt% and 30 wt %.

In one embodiment, the amide-type local anesthetic is present in thecomposition at between about 0.01 wt % and about 7.5 wt %. In anotherembodiment, the amide-type local anesthetic is present in thecomposition at between about 0.1 wt % and about 7.5 wt %, or betweenabout 0.1 wt % and about 5.5 wt %, or between about 0.25 wt % and about5.2 wt %, or between about 0.25 wt % and about 5.0 wt %.

Enolic-Acid Non-Steroidal Anti-Inflammatory Drug (NSAID)

The compositions, in some embodiments, provided herein additionallycomprise an NSAID (non-steroidal anti-inflammatory drug). NSAIDscontemplated for use in the compositions include acetic acidderivatives, propionic acid derivatives, enolic acid derivatives andfenamic acid derivatives. Representative NSAIDS in these classesinclude, but are not limited to, the following acetic acid-type NSAIDs:diflunisal, indomethacin, tolmetin, sulindac, etodolac, ketorolac,diclofenac and nabumetone; the following propionic acid-type NSAIDs:ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen,dexketoprofen, flurbiprofen, oxaprozin, and loxoprofen; fenamicacid-type NSAIDs: mefenamic acid, meclofenamic acid, flufenamic acid andtolfenamic acid.

In one embodiment, the NSAID in the composition is an enolic acid-typeNSAID. As described herein, the incorporation of an enolic acid NSAID inthe compositions is effective to alter the pharmacodynamic profile ofthe resulting composition, to thereby provide a composition that isgenerally effective to provide pain relief from about 1 day to at leastabout 5 days following application, in contrast to the short-actingnature of the composition absent the enolic-acid NSAID. Additionalfeatures of the composition are described elsewhere herein.

The NSAID included in the composition, i.e., the enolic-acid NSAID, doesnot comprise a carboxylic acid function as do most NSAIDs, but is weaklyacidic in nature due to the presence of a vinylogous carboxylic acidthat can undergo keto-enol tautomerism. Representative enolic-acidNSAIDs suitable for inclusion in the instant compositions includemeloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam. Ina particular embodiment, the enolic-acid NSAID is meloxicam. Oneparticularly particular composition comprises bupivacaine and meloxicam.Yet another particular composition comprises ropivacaine and meloxicam.

While not being bound in theory, it is believed that the incorporationof the enolic-acid NSAID is effective to reduce the inflammation thatoccurs as a result of a typical operative procedure, to thereby allowthe amide-type anesthetic to provide effective local anesthesia. Morespecifically, it is believed that the slight drop of pH in tissues thatoften accompanies inflammation, e.g., in a post-operative patient, maybe responsible for the inability of the amino-amide-type anesthetic toprovide effective pain relief after about 5 hours or so. Due to the lagtime in the inflammatory response, the local anesthetic is able toprovide significant, short-term pain relief post-surgery. However, it iscontemplated that once inflammation occurs to a degree effective to dropthe pH of target tissues to a degree sufficient to prevent theamide-type local anesthetic from exerting its desired pharmacologicaleffect, i.e., by impeding the ability of the anesthetic to be deliveredto target nerves, the composition then becomes significantly lesseffective in its ability to provide effective pain relief. Thus, it isbelieved that the observed short-term effect of composition absent theNSAID is not strictly due to the inability of the composition to releasethe local anesthetic, but rather, is due to the inability of thereleased local anesthetic to exert its intended pharmacological effect.Interestingly, it appears that not all NSAIDs are effective in enhancingthe effect of a locally administered amide-type anesthetic. As describedin Example 7, an illustrative composition comprising a polyorthoester asa delivery vehicle and bupivacaine and 7.5 wt % diclofenac (having aproton-donating carboxylic acid group) failed to regain its short-termefficacy after about 1 day following application or more, and providedsignificantly less pain relief over the time frame of 1 to 5 daysfollowing application when compared to its early, short-term efficacy upto about 5 hours post-application. This is in distinct contrast to thebupivacaine-meloxicam composition.

The enolic-acid NSAID is dissolved or dispersed into the composition asprovided herein. The concentration of the enolic-acid NSAID such asmeloxicam may vary in the composition from about 0.01 wt % to 10 wt %,0.01 wt % to 5 wt %, 0.01 wt % to 3 wt %, 0.01 wt % to 1 wt %, 0.10 wt %to 10 wt %, 0.1 wt % to 5 wt %, 0.1 wt % to 3 wt %, 0.1 wt % to 1 wt %,and may be 0.01 wt %, 0.011 wt %, 0.012 wt %, 0.013 wt %, 0.014 wt %,0.015 wt %, 0.016 wt %, 0.017 wt %, 0.018 wt %, 0.019 wt %, 0.02 wt %,0.021 wt %, 0.022 wt %, 0.023 wt %, 0.024 wt %, 0.025 wt %, 0.026 wt %,0.027 wt %, 0.028 wt %, 0.029 wt %, 0.030 wt %, 0.031 wt %, 0.032 wt %,0.033 wt %, 0.034 wt %, 0.035 wt %, 0.036 wt %, 0.037 wt %, 0.038 wt %,0.039 wt %, 0.040 wt %, 0.041 wt %, 0.042 wt %, 0.043 wt %, 0.044 wt %,0.045 wt %, 0.046 wt %, 0.047 wt %, 0.048 wt %, 0.049 wt %, 0.05 wt %,0.051 wt %, 0.052 wt %, 0.053 wt %, 0.054 wt %, 0.055 wt %, 0.056 wt %,0.057 wt %, 0.058 wt %, 0.059 wt %, 0.06 wt %, 0.061 wt %, 0.062 wt %,0.063 wt %, 0.064 wt %, 0.065 wt %, 0.066 wt %, 0.067 wt %, 0.068 wt %,0.069 wt %, 0.07 wt %, 0.071 wt %, 0.072 wt %, 0.073 wt %, 0.074 wt %,0.075 wt %, 0.076 wt %, 0.077 wt %, 0.078 wt %, 0.079 wt %, 0.08 wt %,0.081 wt %, 0.082 wt %, 0.083 wt %, 0.084 wt %, 0.085 wt %, 0.086 wt %,0.087 wt %, 0.088 wt %, 0.089 wt %, 0.09 wt %, 0.091 wt %, 0.092 wt %,0.093 wt %, 0.094 wt %, 0.095 wt %, 0.096 wt %, 0.097 wt %, 0.098 wt %,0.099 wt %, 0.1 wt %, 0.11 wt %, 0.12 wt %, 0.13 wt %, 0.14 wt %, 0.15wt %, 0.16 wt %, 0.17 wt %, 0.18 wt %, 0.19 wt %, 0.2 wt %, 0.21 wt %,0.22 wt %, 0.23 wt %, 0.24 wt %, 0.25 wt %, 0.26 wt %, 0.27 wt %, 0.28wt %, 0.29 wt %, 0.30 wt %, 0.31 wt %, 0.32 wt %, 0.33 wt %, 0.34 wt %,0.35 wt %, 0.36 wt %, 0.37 wt %, 0.38 wt %, 0.39 wt %, 0.40 wt %, 0.41wt %, 0.42 wt %, 0.43 wt %, 0.44 wt %, 0.45 wt %, 0.46 wt %, 0.47 wt %,0.48 wt %, 0.49 wt %, 0.5 wt %, 0.5.1 wt %, 0.52 wt %, 0.53 wt %, 0.54wt %, 0.55 wt %, 0.56 wt %, 0.57 wt %, 0.58 wt %, 0.59 wt %, 0.6 wt %,0.61 wt %, 0.62 wt %, 0.63 wt %, 0.64 wt %, 0.65 wt %, 0.66 wt %, 0.67wt %, 0.68 wt %, 0.69 wt %, 0.7 wt %, 0.71 wt %, 0.72 wt %, 0.73 wt %,0.74 wt %, 0.75 wt %, 0.76 wt %, 0.77 wt %, 0.78 wt %, 0.79 wt %, 0.8 wt%, 0.81 wt %, 0.82 wt %, 0.83 wt %, 0.84 wt %, 0.85 wt %, 0.86 wt %,0.87 wt %, 0.88 wt %, 0.89 wt %, 0.9 wt %, 0.91 wt %, 0.92 wt %, 0.93 wt%, 0.94 wt %, 0.95 wt %, 0.96 wt %, 0.97 wt %, 0.98 wt %, 0.99 wt %, 1.0wt %, 1.01 wt %, 1.02 wt %, 1.03 wt %, 1.04 wt %, 1.05 wt %, 1.06 wt %,1.07 wt %, 1.08 wt %, 1.09 wt %, 1.1 wt %, 1.11 wt %, 1.12 wt %, 1.13 wt%, 1.14 wt %, 1.15 wt %, 1.16 wt %, 1.17 wt %, 1.18 wt %, 1.19 wt %, 1.2wt %, 1.21 wt %, 1.22 wt %, 1.23 wt %, 1.24 wt %, 1.25 wt %, 1.26 wt %,1.27 wt %, 1.28 wt %, 1.29 wt %, 1.30 wt %, 1.31 wt %, 1.32 wt %, 1.33wt %, 1.34 wt %, 1.35 wt %, 1.36 wt %, 1.37 wt %, 1.38 wt %, 1.39 wt %,1.40 wt %, 1.41 wt %, 1.42 wt %, 1.43 wt %, 1.44 wt %, 1.45 wt %, 1.46wt %, 1.47 wt %, 1.48 wt %, 1.49 wt %, 1.5 wt %, 1.5.1 wt %, 1.52 wt %,1.53 wt %, 1.54 wt %, 1.55 wt %, 1.56 wt %, 1.57 wt %, 1.58 wt %, 1.59wt %, 1.6 wt %, 1.61 wt %, 1.62 wt %, 1.63 wt %, 1.64 wt %, 1.65 wt %,1.66 wt %, 1.67 wt %, 1.68 wt %, 1.69 wt %, 1.7 wt %, 1.71 wt %, 1.72 wt%, 1.73 wt %, 1.74 wt %, 1.75 wt %, 1.76 wt %, 1.77 wt %, 1.78 wt %,1.79 wt %, 1.8 wt %, 1.81 wt %, 1.82 wt %, 1.83 wt %, 1.84 wt %, 1.85 wt%, 1.86 wt %, 1.87 wt %, 1.88 wt %, 1.89 wt %, 1.9 wt %, 1.91 wt %, 1.92wt %, 1.93 wt %, 1.94 wt %, 1.95 wt %, 1.96 wt %, 1.97 wt %, 1.98 wt %,1.99 wt %, 2.00 wt %, 2.01 wt %, 2.02 wt %, 2.03 wt %, 2.04 wt %, 2.05wt %, 2.06 wt %, 2.07 wt %, 2.08 wt %, 2.09 wt %, 2.1 wt %, 2.11 wt %,2.12 wt %, 2.13 wt %, 2.14 wt %, 2.15 wt %, 2.16 wt %, 2.17 wt %, 2.18wt %, 2.19 wt %, 2.20 wt %, 2.21 wt %, 2.22 wt %, 2.23 wt %, 2.24 wt %,2.25 wt %, 2.26 wt %, 2.27 wt %, 2.28 wt %, 2.29 wt %, 2.30 wt %, 2.31wt %, 2.32 wt %, 2.33 wt %, 2.34 wt %, 2.35 wt %, 2.36 wt %, 2.37 wt %,2.38 wt %, 2.39 wt %, 2.40 wt %, 2.41 wt %, 2.42 wt %, 2.43 wt %, 2.44wt %, 2.45 wt %, 2.46 wt %, 2.47 wt %, 2.48 wt %, 2.49 wt %, 2.5 wt %,2.5.1 wt %, 2.52 wt %, 2.53 wt %, 2.54 wt %, 2.55 wt %, 2.56 wt %, 2.57wt %, 2.58 wt %, 2.59 wt %, 2.6 wt %, 2.61 wt %, 2.62 wt %, 2.63 wt %,2.64 wt %, 2.65 wt %, 2.66 wt %, 2.67 wt %, 2.68 wt %, 2.69 wt %, 2.7 wt%, 2.71 wt %, 2.72 wt %, 2.73 wt %, 2.74 wt %, 2.75 wt %, 2.76 wt %,2.77 wt %, 2.78 wt %, 2.79 wt %, 2.8 wt %, 2.81 wt %, 2.82 wt %, 2.83 wt%, 2.84 wt %, 2.85 wt %, 2.86 wt %, 2.87 wt %, 2.88 wt %, 2.89 wt %, 2.9wt %, 2.91 wt %, 2.92 wt %, 2.93 wt %, 2.94 wt %, 2.95 wt %, 2.96 wt %,2.97 wt %, 2.98 wt %, 2.99 wt %, 3.0 wt %, 3.01 wt %, 3.02 wt %, 3.03 wt%, 3.04 wt %, 3.05 wt %, 3.06 wt %, 3.07 wt %, 3.08 wt %, 3.09 wt %, 3.1wt %, 3.11 wt %, 3.12 wt %, 3.13 wt %, 3.14 wt %, 3.15 wt %, 3.16 wt %,3.17 wt %, 3.18 wt %, 3.19 wt %, 3.20 wt %, 3.21 wt %, 3.22 wt %, 3.23wt %, 3.24 wt %, 3.25 wt %, 3.26 wt %, 3.27 wt %, 3.28 wt %, 3.29 wt %,3.30 wt %, 3.31 wt %, 3.32 wt %, 3.33 wt %, 3.34 wt %, 3.35 wt %, 3.36wt %, 3.37 wt %, 3.38 wt %, 3.39 wt %, 3.40 wt %, 3.41 wt %, 3.42 wt %,3.43 wt %, 3.44 wt %, 3.45 wt %, 3.46 wt %, 3.47 wt %, 3.48 wt %, 3.49wt %, 3.5 wt %, 3.5.1 wt %, 3.52 wt %, 3.53 wt %, 3.54 wt %, 3.55 wt %,3.56 wt %, 3.57 wt %, 3.58 wt %, 3.59 wt %, 3.6 wt %, 3.61 wt %, 3.62 wt%, 3.63 wt %, 3.64 wt %, 3.65 wt %, 3.66 wt %, 3.67 wt %, 3.68 wt %,3.69 wt %, 3.7 wt %, 3.71 wt %, 3.72 wt %, 3.73 wt %, 3.74 wt %, 3.75 wt%, 3.76 wt %, 3.77 wt %, 3.78 wt %, 3.79 wt %, 3.8 wt %, 3.81 wt %, 3.82wt %, 3.83 wt %, 3.84 wt %, 3.85 wt %, 3.86 wt %, 3.87 wt %, 3.88 wt %,3.89 wt %, 3.9 wt %, 3.91 wt %, 3.92 wt %, 3.93 wt %, 3.94 wt %, 3.95 wt%, 3.96 wt %, 3.97 wt %, 3.98 wt %, 3.99 wt %, 4.0 wt %, 4.25 wt %, 4.5wt %, 4.75 wt %, 5.0 wt %, 5.25 wt %, 5.5 wt %, 5.75 wt %, 6.0 wt %,6.25 wt %, 6.5 wt %, 6.75 wt %, 7.0 wt %, 7.25 wt %, 7.5 wt %, 7.75 wt%, 8.0 wt %, 8.25 wt %, 8.5 wt %, 8.75 wt %, 9.0 wt %, 9.25 wt %, 9.5 wt%, 9.75 wt %, or 10.0 wt %.

In one embodiment, the composition comprises an enolic-acid NSAID in anamount above about 0.01 wt % of the composition, above about 0.025 wt %,about 0.05 wt %, above about 0.1 wt % of the composition, or above about0.25 wt %, or between about 0.01-10 wt %, or between about 0.01-7.5 wt%, or between about 0.01-5.0 wt %, or between about 0.01-3.5 wt %.

Exemplary Delivery Vehicles

The composition additionally comprises a delivery vehicle. In oneembodiment, the delivery vehicle is a sustained-release vehicle, andexemplary vehicles include polymeric formulations, liposomes,microspheres, implantable device or non-polymeric formulations. Examplesof these vehicles will now be described.

Liposomes

Liposomes are small vesicles composed of lipids arranged in sphericalbilayers. Liposomes are usually classified as small unilamellar vesicles(SUV), large unilamellar vesicles (LUV), multi-lamellar vesicles (MLV)or multivesicular liposomes (MVL). SUVs and LUVs, by definition, haveonly one bilayer, whereas MLVs contain many concentric bilayers (see,e.g., Stryer, Biochemistry, 2d Edition, W.H. Freeman & Co., p. 213(1981)). MVLs were first reported by Kim et al. (Biochim, Biophys. Acta,728:339-348, 1983) and contain multiple, non-concentric aqueous chambersper particle (See, U.S. Pat. Nos. 6,132,766 and 8,182,835, incorporatedherein by reference in their entirety).

Liposomes suitable for use in the composition of the present inventioninclude those composed primarily of vesicle-forming lipids.Vesicle-forming lipids can form spontaneously into bilayer vesicles inwater, as exemplified by the phospholipids. The liposomes can alsoinclude other lipids incorporated into the lipid bilayers, e.g.,cholesterol, with the hydrophobic moiety in contact with the interior,hydrophobic region of the bilayer membrane, and the head group moietyoriented toward the exterior, polar surface of the bilayer membrane.

The vesicle-forming lipids can have two hydrocarbon chains, typicallyacyl chains, and a head group, either polar or nonpolar. There are avariety of synthetic vesicle-forming lipids and naturally-occurringvesicle-forming lipids, including the phospholipids, such asphosphalidylcholine, phosphatidylethanolamine, phosphatidic acid,phosphatidylinositol, and sphingomyelin, where the two hydrocarbonchains are typically between about 14-22 carbon atoms in length, andhave varying degrees of unsaturation. The above-described lipids andphospholipids whose acyl chains have varying degrees of saturation canbe obtained commercially or prepared according to published methods.Other suitable lipids include glycolipids and sterols, such ascholesterol.

In one embodiment, the vesicle-forming lipid is selected to achieve aspecified degree of fluidity or rigidity, to control the stability ofthe liposome in serum and to control the rate of release of theentrapped agent in the liposome. Liposomes may be prepared by a varietyof techniques (see, e.g., Szoka, F., Jr., et al., Ann. Rev. Biophys.Bioeng. 9:467 (1980); U.S. Pat. No. 5,631,018). It will be appreciatedthat lipid-based delivery vehicles other than liposomes arecontemplated, such as micelles and emulsions.

In one embodiment, the amide-type local anesthetic and the enolic-acidNSAID are entrapped in an aqueous space of the liposome or in a lipidlayer of the liposome.

Microspheres/Microparticles/Microcapsules

In another embodiment, the delivery vehicle is a microspheres,microparticles or microcapsules. Microspheres in the form of sphericalpolymer matrices with interconnected pores in which an active agent isincorporated are described, for example, in U.S. Pat. No. 4,818,542.Microparticles comprised of one or more polymers in which the activeagents are incorporated or associated can be fabricated frombiodegradable or non-biodegradable polymers that are suitable for invivo use, such as poly(vinylpyrrolidone) and poly(acrylamide). Themicrospheres or microparticles can be administered as part of aformulation that forms a depot in situ or as part of an implant. Theactive agents are released from the microspheres or microparticles in acontrolled fashion, to provide the desired therapeutic efficacy. In oneembodiment, the sustained-release delivery vehicle is a microspherecomprised of a bioerodible or biodegradable polymer. In anotherembodiment, the amide-type local anesthetic and the enolic-acid NSAIDare entrapped in the microsphere.

Implantable Devices

Implantable devices with a reservoir in which the active agents arecontained and controllably-released are known in the medical arts. Inone embodiment, an osmotic, mechanical, or electromechanical device isprovided for implantation and sustained release of the active agents.Examples of implantable devices are set forth in U.S. Pat. Nos.7,655,254; 8,603,051; and 8,603,076 and US Publication No. 2003/0032947.

Non-Polymeric Formulations

The delivery vehicle can also take the form of a non-polymeric,pharmaceutically acceptable carrier. For example, the non-polymericformulation can comprise sucrose acetate isobutyrate as a non-polymeric,pharmaceutically acceptable carrier and an optional solvent, such asbenzyl alcohol. The non-polymeric formulation can be a liquid. Thisliquid, non-polymeric formulation provides sustained local anesthesia toa subject after administration for a period of about 24-36 hours, 36-48hours, 48-60 hours, 60-72 hours, 3-4 days or 3-5 days. In oneembodiment, the delivery vehicle is comprised of between about 50-80 wt% sucrose acetate isobutyrate and between about 5-25 wt % benzylalcohol, alternatively between 55-75 wt % sucrose acetate isobutyrateand between about 15-25 wt % benzyl alcohol, with the remainder to 100wt % being the active agents. Exemplary non-polymeric formulations ofthis type are described in EP 1809329, which is incorporated herein byreference in its entirety.

In some embodiments, the liquid non-polymeric carrier is a liquidcarrier material having a viscosity of about less than 50,000 mPa-s at37° C., measured using a viscometer. Alternatively, the carrier has aviscosity of less than about 10,000 mPa-s when measured at 37° C. usinga viscometer. In another embodiment, the liquid non-polymeric carrier isa liquid carrier material having a viscosity of about less than 5,000mPa-s at 37° C. In yet another embodiment, the liquid non-polymericcarrier is a liquid carrier material having a viscosity of about lessthan 2,500 mPa-s at 37° C.

In another embodiment, the non-polymeric formulation is an aqueoussolution.

Polymeric Formulations

Exemplary polymeric formulations as the sustained-release deliveryvehicle include those comprised of bioerodible or biodegradablepolymers. The vehicle when comprised of a bioerodible or biodegradablepolymer can be a solid or a semi-solid vehicle. Bioerodible and/orbiodegradable polymers are known in the art, and include but are notlimited to polylactides, polyglycolides, poly(lactic-co-glycolic acid)copolymers, polycaprolactones, poly-3-hydroxybutyrate, andpolyorthoesters. Semisolid polymers exist either in a glassy or viscousliquid state. Semisolid polymers typically display a glass transitiontemperature (Tg) below room temperature. Below the Tg, semisolidpolymers can be considered to exist in a glassy state, while above theTg, the polyorthoester can be considered to exist in a liquid state.Semisolid polyorthoester polymers are not thermoplastic polymers.

In one embodiment, a bioerodible or biodegradable polymer is selected toprovide a certain rate of degradation or erosion to achieve a desiredrelease rate of the enolic acid-type NSAID and the amide- or anilidetype anesthetic. The delivery vehicle and active agents can beformulated to provide a semi-solid or solid composition. By way ofexample, in one embodiment, a semi-solid delivery vehicle comprised of apolyorthoester is provided, and some examples are set forth herein. Inanother embodiment, the polymeric delivery vehicle forms an implant ordepot in situ.

In another embodiment, a solid delivery vehicle comprised of abiodegradable or bioerodible polymer is provided, where the solidvehicle is in the form of a rod or disk. Rods and disks are suitable forimplantation into a patient, and the biodegradable or bioerodiblepolymer in which the active agents are incorporated can formulated totailor the release of active agent. For example, the rod or disk can beformulated from different polymers with different rates ofbiodegradability or polymers of differing molecular weights can be used,as well as additives or excipients can be added to active agent-polymermatrix to tailor the rate of agent release. The rod or disk can alsocomprise materials commonly used in sutures and/or capable of being usedin sutures, including the biodegradable polymers noted above as well aspolyglactin and copolymers of glycolide with trimethylene carbonate(TMC) (polyglyconate).

In one embodiment, the delivery vehicle is comprised of apolyorthoester.

Polyorthoesters useful for the compositions provided herein aregenerally composed of alternating residues resulting from reaction of adiketene acetal and a diol, where each adjacent pair of diketene acetalderived residues is separated by the residue of a reacted diol. Thepolyorthoester may comprise α-hydroxy acid-containing subunits, i.e.,subunits derived from an α-hydroxy acid or a cyclic diester thereof,such as subunits comprising glycolide, lactide, or combinations thereof,i.e., poly(lactide-co-glycolide), including all ratios of lactide toglycolide, e.g., 75:25, 65:35, 50:50, etc. Such subunits are alsoreferred to as latent acid subunits; these latent acid subunits alsofall within the more general “diol” classification as used herein, dueto their terminal hydroxyl groups. Polyorthoesters can be prepared asdescribed, for example, in U.S. Pat. Nos. 4,549,010 and 5,968,543.Exemplary polyorthoesters suitable for use in the compositions providedherein are described in U.S. Pat. No. 8,252,304.

The mole percentage of α-hydroxy acid containing subunits, R¹, generallyranges from 0 to 20 mol % of the total diol components (R¹ and R³ asprovided below). In one or more embodiments, the mole percentage ofα-hydroxy acid containing subunits in the polyorthoester formulation isat least about 0.01 mole percent. Exemplary percentages of α-hydroxyacid containing subunits in the polymer are from about 0 to about 50mole percent, or from about 0 to about 25 mole percent, or from about0.05 to about 30 mole percent, or from about 0.1 to about 25 molepercent. For example, in one embodiment, the percentage of α-hydroxyacid containing subunits in the polymer is from about 0 to about 50 molepercent. In another embodiment, the percentage of α-hydroxy acidcontaining subunits in the polymer is from about 0 to about 25 molepercent. In yet another particular embodiment, the percentage ofα-hydroxy acid containing subunits in the polymer is from about 0.05 toabout 30 mole percent. In yet another embodiment, the percentage ofα-hydroxy acid containing subunits in the polymer is from about 0.1 toabout 25 mole percent. As an illustration, the percentage of α-hydroxyacid containing subunits may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 24, 26, 27, 28, 29or 30 mole percent, including any and all ranges lying therein, formedby combination of any one lower mole percentage number with any highermole percentage number.

More particularly, a poly(orthoester) for use in the compositions anddelivery systems provided herein is described by the following formula:

where: R* is a C₁₋₄ alkyl (e.g., C1, C2, C3 or C4 alkyl), n is aninteger ranging from 5 to 400, and A in each subunit is R¹ or R³. Thatis, in any monomer unit

of the polymer of Formula I, A may be either R¹ or R³.

In a particular embodiment, R* is ethyl (i.e., C2 alkyl). A subunit inaccordance with formula I, wherein R* is ethyl, corresponds to a subunitresulting from reaction of a diol as provided herein with3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU), adiketene acetal having the structure:

In reference to Formula I, as described previously, A may correspond toR¹. R¹ is

where p and q are each independently integers that range from betweenabout 1 to 20 (e.g., are each independently selected from 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20), each R⁵ isindependently hydrogen or C₁₋₄ alkyl (e.g., is H, or C1, C2, C3, or C4alkyl); and R⁶ is:

where s is an integer from 0 to 10 (e.g., is selected from, 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10); t is an integer from 2 to 30; and R⁷ is hydrogenor C₁₋₄ alkyl (e.g., is H or C1, C2, C3, or C4 alkyl). In one or moreparticular embodiments, R⁷ is H. The R¹ subunits are α-hydroxyacid-containing subunits, i.e., subunits derived from an α-hydroxy acidor a cyclic diester thereof.

In reference to Formula I, A may also correspond to R³, where R³ is:

and x is an integer ranging from 1 to 100, and is, in certain particularinstances, selected from 1, 2, 3, 4, and 5; y is an integer in a rangefrom 2 to 30; and R⁸ is hydrogen or C₁₋₄ alkyl (C1, C2, C3 or C4 alkyl).

In a particular embodiment, R⁸ is H.

In some embodiments, the poly(orthoester) is one in which A is R¹ or R³,where R¹ is

where p and q are each independently integers that range from betweenabout 1 and 20, where the average number of p or the average number ofthe sum of p and q (p+q) is between about 1 and 7 (e.g., 1, 2, 3, 4, 5,6, 7) when R¹ is present in the poly(orthoester) polymer; x and s areeach independently an integer ranging from 0 to 10; and t and y are eachindependently an integer ranging from 2 to 30. In one or more particularembodiments, R⁵ is H.

Additional particular poly(orthoesters) are those in which A is R¹ orR³, where R¹ is

and p and q are each independently integers that vary from between about1 and 20, or between about 1 and 15, or between about 1 and 10, wherethe average number of p or the average number of the sum of p and q(i.e., p+q) is between about 1 and 7 when R1 is present in thepoly(orthoester) polymer. Additionally, particular ranges of x and s (inreference to the particular embodiment above or in reference to anypolyorthoester as provided herein) are those in which each isindependently an integer ranging from 0 to 7 or from 1 to 5. Similarly,particular ranges for t and y are those in which each independentlyvaries from 2 to 10.

Particular polyorthoesters are those in which R⁵ is hydrogen or methyl.

In certain particular embodiments, s and x are each independentlyselected from 1, 2, 3, 4, 5, 6, 7 and 8. In some particular embodiments,s is 2. In some other particular embodiments, x is 2.

An exemplary polyorthoester comprises alternating residues of3,9-diethyl-3,9-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl and A:

where A is as described above.

Polyorthoesters such as those described herein can be prepared byreacting an illustrative diketene acetal,3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU),

with one or more diols as described above, such as HO—R¹—OH or HO—R³—OH.Illustrative diols include oligoethylene glycols such as triethyleneglycol (TEG), oligoethylene glycols modified at one or both termini withan α-hydroxy acid such as an oligoethylene glycol diglycolide or anoligoethylene glycol dilactide, organic diols having a hydrocarbyl coreof from 2 to 30 carbon atoms such as 1,6-hexanediol, 1,10-decanediol,cis/trans 1,4-cyclohexane dimethanol, para-menthane-3,8-diol,1,4-butanediol, 1,5-pentanediol, 1,7-heptanediol, 1,8-octanediol,1,10-decanediol, 1,12-dodecanediol, and cyclic equivalents thereof,where the hydroxyl groups can be at any two positions within thecycloalkyl or alkylene ring. An organic diol can possess from 2 to 20carbon atoms. The organic diol can be linear, branched or cyclic, andmay also be saturated or unsaturated. Generally, unsaturated diols willpossess from 1-3 elements of unsaturation. A particular poly(orthoester)will contain from about from 10 to 50 total mole percent of subunitsderived from one or more organic diols having a hydrocarbyl core.

Diols such as HO—R¹—OH are prepared as described in U.S. Pat. No.5,968,543 and in Heller et al., J. Polymer Sci., Polymer Letters Ed.18:293-297 (1980). For example, a diol of the formula HO—R¹-0Hcomprising a polyester moiety can be prepared by reacting a diol of theformula HO—R³—OH with between 0.5 and 10 molar equivalents of a cyclicdiester of an α-hydroxy acid such as lactide or glycolide, and allowingthe reaction to proceed at 100-200° C. for about 12 hours to about 48hours. Suitable solvents for the reaction include organic solvents suchas dimethylacetamide, dimethyl sulfoxide, dimethylformamide,acetonitrile, pyrrolidone, tetrahydrofuran, and methylbutyl ether.Although the diol product is generally referred to herein as a discreteand simplified entity, e.g., TEG diglycolide (and diol reaction productssuch as TEG diglycolide), it will be understood by those of skill in theart that due to the reactive nature of the reactants, e.g., ring openingof the glycolide, the diol is actually a complex mixture resulting fromthe reaction, such that the term, TEG diglycolide (or any other termreferring a similar product), generally refers to the average or overallnature of the product.

A particular polyorthoester is prepared by reacting3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU) with oneor more reactive diols. Generally, the polyorthoester is prepared byreacting DETOSU with two or more reactive diols under anhydrousconditions. A particular polyorthoester is prepared by reacting DETOSUwith triethylene glycol and triethylene glycol diglycolide as describedin U.S. Pat. No. 8,252,305. A particular polyorthoester prepared fromDETOSU-triethylene glycol-triethylene glycol diglycolide possesses thefollowing molar ratios of components: 90:80:20, although the relativeratios of components can be suitably varied as described above.

A polyorthoester formed by the reaction of DETOSU with TEG and TEGdiglycolide can generally be described as possessing the followingsubunits, where R¹ corresponds to the diolate portion derived fromtriethylene glycol diglycolide (formed by reaction of glycolide withTEG) and R³ corresponds to the diolate portion derived from triethyleneglycol:

where A is R¹, and R¹ is

where R⁵ is H and R⁶ is

the resulting component of the polyorthoester is:

where the sum of p and q is, on average, 2 and s is 2; and when A is R³,and R³ is

where x is 2, the resulting subunit or component of the polyorthoesteris:

Structures corresponding to polyorthoesters prepared from the variousα-hydroxy acid-containing subunits and additional diols described hereincan be readily envisioned.

Exemplary polyorthoesters possess a weight average molecular weight ofabout 1000 Da to about 200,000 Da, for example from about 2,500 Da toabout 100,000 Da or from about 3,500 Da to about 20,000 Da or from about4,000 Da to about 10,000 Da or from about 5,000 Da to about 8,000 Da.Illustrative molecular weights, in Da, are 2500, 5000, 5500, 6000, 6500,7000, 7500, 8000, 8500, 9000, 9500, 10,000, 20,000, 30,000, 40,000,50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 120,000, 150,000,175,000 and 200,000, and ranges therein, wherein exemplary rangesinclude those formed by combining any one lower molecular weight asdescribed above with any one higher molecular weight as provided above,relative to the selected lower molecular weight.

In one particular embodiment related to the polyorthoester in thedelivery system, the polyorthoester has a molecular weight ranging fromabout 2,500 daltons to 10,000 daltons.

In one embodiment, the poly(orthoesters) described in this section aresemi-solids both at room temperature and at temperatures above roomtemperature. In one embodiment, polyorthoesters containing 80 to 100mole % R³, where R³ is

where x is 2, are semisolid polymers at both room temperature and attemperatures above room temperature. Semisolid polymers exist either ina glassy or viscous liquid state. Semisolid polymers typically display aglass transition temperature (Tg) below room temperature. Below the Tg,semisolid polymers can be considered to exist in a glassy state, whileabove the Tg, the polyorthoester can be considered to exist in a liquidstate. Semisolid polyorthoester polymers are not thermoplastic polymers.

Generally, polyorthoesters in accordance with any one of the followingformulae, Formula I, Formula II, Formula III or Formula IV, are suitablefor use in the compositions and/or delivery vehicles provided herein:

In reference to formulas I-IV,

R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a is aninteger from 1 to 12 (e.g., selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, and 12), and b and c are independently integers from 1 to 5 (e.g.,selected from 1, 2, 3, 4, and 5);R* is a C₁₋₄ alkyl;R^(o), R″ and R′″ are each independently H or C₁₋₄ alkyl;n is an integer of at least 5; andA is a diol.

For example, the compositions and delivery systems described herein maybe comprised of a polyorthoester of Formula I, Formula II, Formula IIIor Formula IV, where: R is a bond, —(CH₂)_(a)—, or—(CH₂)_(b)—O—(CH₂)_(c)—; where a is an integer of 1 to 12, and b and care independently integers of 1 to 5;

R* is a C₁₋₄ alkyl;R^(o), R″ and R′″ are each independently H or C₁₋₄ alkyl;n is an integer of at least 5; andA is R¹, R², R³, or R⁴, whereR¹ is an α-hydroxy acid containing subunit as described in the precedingparagraphs;R⁵ is hydrogen or C₁₋₄ alkyl (e.g., methyl, ethyl, propyl, butyl,isopropyl, isobutyl, sec-butyl); and R⁶ is selected from the groupconsisting of:

where:s is an integer ranging from 0 to 10;t is an integer ranging from 2 to 30; andR⁷ is hydrogen or C₁₋₄ alkyl;

R² is:

R³ is:

where:x is an integer ranging from 0 to 200;y is an integer ranging from 2 to 30;R⁸ is hydrogen or C₁₋₄ alkyl;R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene; andR⁴ is the residue of a diol containing at least one functional groupindependently selected from an amide, an imide, a urea, and a urethane(carbmate) group.

In certain instances, the polyorthoester is one according to any one ofFormulae I-IV in which A is R¹, R³, or R⁴, where

R³ is selected from:

where:x is an integer of 0 to 100;y is an integer of 2 to 30;R⁸ is hydrogen or C₁₋₄ alkyl;R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene;R⁴ is a residual of a diol containing at least one functional groupindependently selected from amide, imide, urea and urethane groups; andR⁵ is hydrogen or C₁₋₄ alkyl.

In one particular embodiment of the polyorthoester, the fraction of theA units that are of the formula R¹ is between 0 and 20 mole percent.

One exemplary polyorthoester is described by formula I, II, III or IV,where:

none of the units have A equal to R²;

R³ is:

where:x is an integer of 1 to 100;y is an integer of 2 to 30; and

R⁶ is:

where:s is an integer of 1 to 10;t is an integer of 2 to 30; andR⁵, R⁷, and R⁸ are independently hydrogen or methyl.

An additional representative polyorthoester of Formula I, II, III or IV,is one in which R³ and R⁶ are both —(CH₂—CH₂—O)₂—(CH₂—CH₂)—; R⁵ ismethyl; and where p and q are each independently selected from 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

In another embodiment of a polyorthoester of Formula I, II, III or IV,R³ and R⁶ are both —(CH₂—CH₂—O)₉—(CH₂—CH₂)—; R⁵ is methyl; and p or thesum of p and q is on average 2.

In another variation, the polyorthoester is of Formula I, II, III or IV,R is —(CH₂)_(b)—O—(CH₂)_(c)—; where b and c are both 2; R* is a C₂alkyl.

Additional representative polyorthoesters of Formula I, II, III or IV,are those in which R⁵ is hydrogen or methyl; R⁶ is

where s is an integer from 1 to 10, or in some embodiments s is selectedfrom 1, 2, 3, or 4; t is an integer from 2 to 30, particularly selectedfrom 2, 3, 4, 5, 6, 7, 8, 9 and 10; R⁷ is hydrogen or methyl; and R³ is

where x is an integer from 1 to 10, or in some embodiments is selectedfrom 1, 2, 3, or 4; y is an integer from 2 to 30, particularly selectedfrom 2, 3, 4, 5, 6, 7, 8, 9 and 10; R⁸ is hydrogen or methyl; R⁴ isselected from a residue of an aliphatic diol having from 2-20 carbonatoms (e.g., selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, and 20 carbon atoms), and in some embodiments R⁴ hasfrom 2 to 10 carbon atoms, interrupted by one or two amide, imide, urea,or urethane groups. In some cases, the proportion of subunits in thepolyorthoester in which A is R¹ is from about 0.01-50 mole percent. Incertain instances, the proportion of subunits in the polyorthoester inwhich A is R¹ is from about 0 to about 30 mole percent, or from about0.1 to 25 mole percent. Illustrative mole percentages include 10, 15, 20and 25 mole percent of subunits in the polyorthoester in which A is R¹.In one embodiment, the mole percent is 20. Additionally, in one or moreembodiments, the proportion of subunits in which A is R² is less thanabout 20 percent, less than about 10 percent, or less than about 5percent, and the proportion of subunits in which A is R⁴ is less than 20percent, less than about 10 percent or less than 5 percent.

The polyorthoester, as shown in Formula I, Formula II, Formula III andFormula IV, in certain embodiments, is one of alternating residues of adiketene acetal and a diol, with each adjacent pair of diketene acetalresidues being separated by the residue of one polyol, such as a diol.

Methods of manufacturing the polyorthoesters are well known in the art,and are described, e.g., in U.S. Pat. Nos. 6,613,355 and 8,252,304.

Optional Solvents and Excipients

The composition may additionally comprise one or more pharmaceuticallyacceptable excipients, and some examples are now set forth.

In the embodiment wherein the delivery vehicle is a polymericformulation, and in particular where the polymer is a polyorthoester,the delivery vehicle may optionally comprise an organic acid, such asthat described in co-owned U.S. Patent Application No. 61/982,300, filedApr. 21, 2014, incorporated herein by reference in its entirety. Theorganic acid facilitates release of the active agent, such as anamide-type local anesthetic, from the vehicle or composition, inparticular, during the early stages of delivery (e.g., days 1-3post-administration). Generally, the organic acid is a carboxylic acid.Most suitable are organic acids having a molecular weight less thanabout 300 daltons. Representative organic acids include, e.g., fumaricor maleic acid, ethanoic acid, propanoic acid, butanoic acid, pentanoicacid, hexanoic acid, heptanoic acid, benzoic acid, salicylic acid andacetyl salicylic acid, oxalic acid, malonic acid, succinic acid,glutaric acid, adipic acid, pimelic acid, and so forth.

The delivery vehicle may comprise from about 0-80 mole percent of amono-carboxylic acid, or from about 0-40 mole percent of a di-carboxylicacid, or from about 0 to 25 a tri-carboxylic acid based upon theconcentration of basic active agent, for example, bupivacaine base. Theamount of the organic acid additive comprised in the vehicle willdepend, at least in part, upon the identity of the particular activeagent, the amount of active agent contained in the vehicle, theparticular polyorthoester, amount thereof, and desired delivery profile.

As discovered by the Applicants, for a given organic acid, vehiclescomprising a greater amount of the organic acid exhibit a faster releaserate which is typically most pronounced during the first 1-3 daysfollowing administration.

In another embodiment, the delivery vehicle in the form of a semi-solidpolyorthoester polymeric formulation may also contain one or more liquidexcipients. The excipient can be a pharmaceutically-acceptablepolyorthoester compatible liquid excipient. Such excipients are liquidat room temperature and are readily miscible with polyorthoesters.Exemplary polyorthoester compatible liquid excipients include bothprotic and aprotic solvents. Protic liquid excipients includepolyethylene glycol having a molecular weight between about 200 Da and4,000 Da, or a polyethylene glycol derivative or co-polymer having amolecular weight between about 200 Da and 4,000 Da, e.g., an end-cappedPEG such as monomethoxypolyethylene glycol, or a mono-, di- ortriglyceride of a C2-C19 aliphatic carboxylic acid or a mixture of suchacids, and alkoxylated tetrahydrofurfuryl alcohols. Additional suitableliquid excipients include C1-C4 alkyl ethers of alkoxylatedtetrahydrofurfuryl alcohols, and C2-C19 aliphatic carboxylic acidesters, or the like. A particular excipient for semi-solid vehicles ismonomethoxy-PEG, having a molecular weight selected from 400, 450, 500,550, 600 and 650 Da.

Additional liquid excipients include aprotic solvents. Aprotic solventssuitable for use, as well as exemplary polyorthoester vehiclescomprising an aprotic solvent are described in U.S. Patent ApplicationPublication No. 2014/0275046, which is incorporated herein by referencein its entirety. Examples of hydrophilic biocompatible, aprotic organicsolvents include, for example, amides such as N-methyl-2-pyrrolidone(NMP), 2-pyrrolidone, N-ethyl-2-pyrrolidone,N-cycylohexyl-2-pyrrolidone, dimethyl acetamide, and dimethyl formamide;esters of monobasic acids such as methyl lactate, ethyl lactate, andmethyl acetate; sulfoxides such as dimethyl sulfoxide anddecylmethylsulfoxide; lactones such as e-caprolactone and butyrolactone;ketones such as acetone and methyl ethyl ketone; and ethers such asdimethyl isosorbide and tetrahydrofuran.

An exemplary semi-solid composition comprises a polyorthoester, a liquidexcipient such as NMP or DMSO, at least one active agent such as anamide-type local anesthetic such as bupivacaine or ropivacaine, and anenolic-acid NSAID such as meloxicam and optionally an organic acidadditive such as maleic acid. The relative concentrations of thecomponents of the semi-solid composition will vary depending upon theamount of the amide-type local anesthetic(s), enolic-acid NSAID,polyorthoester, polyorthoester-compatible liquid excipient, and organicacid additive, if present. The weight percent of the polyorthoestercompatible liquid excipient can range from about 10-50 weight percent,or from about 10-40 weight percent, or from 10-30 weight percent, orfrom 10-25 weight percent. Exemplary amounts of thepolyorthoester-compatible liquid excipient are about 10, 12, 15, 20, 25,30, 35, 40, 45 or 50 weight percent.

In another embodiment, the compositions described herein and inparticular the semi-solid composition comprising a polyorthoester, aliquid excipient such as NMP or DMSO, at least one active agent such asan amide-type local anesthetic such as bupivacaine or ropivacaine, andan enolic-acid NSAID such as meloxicam and optionally an organic acidadditive, additionally comprises a viscosity reducing triglyceridesolvent, such as those set forth in section 2 below and in the amountsset forth in section 2 below.

The delivery vehicle in the form of a semi-solid polymeric formulationcan be prepared by mixing or blending the active agents, the polymer,such as the polyorthoester, an optionalpolymeric/polyorthoester-compatible liquid excipient, and any otheradditional additives or excipients as desired. The mixing or blendingcan be performed by any suitable method, generally at a temperature lessthan about 50° C., e.g., at room temperature, although in certaininstances, depending upon the nature of the materials, mixing orblending may be carried out at higher temperatures, e.g., from about 25to 100° C. The mixing or blending is generally carried out in theabsence of additional solvents, to obtain a homogeneous, flowable andnon-tacky vehicle at room temperature.

The polymeric-compatible liquid excipient is typically added to thecompositions in an amount ranging from about 10 percent to about 70percent by weight, relative to the total weight of the composition. Theliquid excipient may be present in the composition in an amount rangingfrom about 20 percent to about 50 percent by weight. In otherembodiments, the liquid excipient is present in the composition in anamount ranging from about 10-60 wt %, 15-60 wt %, 15-50 wt %, 20-60 wt%, 25-50 wt %, 30-70 wt %, 30-60 wt %, 30-50 wt %, 35-70 wt %, 35-60 wt% or 35-50 wt %.

The rate of release of the active agent (e.g., drug) can be controlledby adjusting the composition and amount of the polymer and/or by theselection and quantity of the optional additives/excipients. Thechemical structure of the polymer (i.e., the type of monomer used or theratio of monomers for copolymers or terpolymers, the end groups on thepolymer chains, and the molecular weight of the polymer) will determinethe hydrophilicity or lipophilicity of the polymer material as well ascontribute to the degradation time of the polymer depot. Morehydrophilic polymers (e.g., polyorthoesters wherein the diol monomer ishydrophilic, e.g., triethylene glycol, tetraethylene glycol, orpolyethylene glycol and the like) are used in applications where fasterrelease rates and shorter durations of release are needed. Thecomposition includes the delivery vehicle and the active agents in anamount effective to provide the desired therapeutic effect over therelease period.

While the singular form is used to describe the polyorthoester and othercomposition components in this application, it is understood that morethan one polyorthoester and/or more than one amide-type local anestheticor enolic-acid NSAID selected from the groups described above may beused in the delivery system. In some embodiments of the herein describedmethods and compositions, the compositions further comprise one or moreadditional excipients. In one embodiment, a particular excipient is onethat does not influence the release of the active agents from thecomposition.

It is also understood that while not required, other pharmaceuticallyacceptable inert agents such as coloring agents and preservatives mayalso be incorporated into the composition.

Aqueous Compositions Comprising a Caine and Enolic-Acid NSAID

As described herein, it was discovered that administering a combinationof an amide-type local anesthetic and an enolic-acid non-steroidalanti-inflammatory drug provides a surprisingly effective level andduration of pain relief in a subject. Based upon the disclosures andguidance provided herein, a person having ordinary skill in the artwould understand that the combination of an amide-type local anestheticand an enolic-acid non-steroidal anti-inflammatory drug would also bemore effective than an equal amount of the an amide-type localanesthetic or the non-steroidal anti-inflammatory drug administeredalone. Accordingly, also disclosed, are aqueous solutions comprising anamide-type local anesthetic and an enolic-acid non-steroidalanti-inflammatory drug. In a particular embodiment, the enolic-acidNSAID in the aqueous composition is meloxicam. In a more particularembodiment, the aqueous composition comprises meloxicam and bupivacaine.

Amide-type local anesthetics which are suitable for the aqueouscombination are commercially available, for example, as injectablesolutions and include but are not limited to lidocaine, mepivacaine,bupivacaine, and etidocaine. Pharmaceutically acceptable solutions ofmeloxicam are disclosed, for example, in U.S. Pat. No. 8,920,820.Accordingly, a pharmaceutically acceptable solution of, for example,meloxicam, can be mixed with a solution of the amide-type localanesthetic prior to administration to a subject. For example, the mixingcan be done less than an hour prior to administration or within 2 hours,4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18hours, 20 hours, 22 hours or 24 hours prior to administration. Themixture of the amide-type local anesthetic with the enolic-acid NSAIDprovides a pain relief which is more effective than the same amount ofeither the amide-type local anesthetic or the enolic-acid NSAID alone.Greater efficacy in providing pain relief of such a combinationformulation can be measured, for example, using the Von Frey assay (suchas that described in Example 8 below), wherein pain tolerance of asubject will be greater when administered a combination of meloxicam andthe amide-type local anesthetic than when administered either activeagent alone.

Accordingly, in one embodiment, an aqueous pharmaceutical compositioncomprising a therapeutically effective amount of meloxicam and atherapeutically effective amount of an amide-type local anesthetic iscontemplated. In one embodiment, administration of the composition to asubject provides pain relief to the subject for a period of about 4 daysto about 6 days after administration.

In another embodiment, an aqueous solution comprising a therapeuticallyeffective amount of meloxicam is provided, wherein the solution issuitable for adding to a pharmaceutical solution comprising atherapeutically effective amount of an amide-type local anesthetic togenerate a mixed solution which is suitable for administering to asubject in need thereof. In one embodiment, administration of the mixedsolution to the subject provides pain relief to the subject for a periodof about 4 hours to about 12 hours after the administration,alternatively for a period of about 4-24 hours, or 2-4 hours, or 2-6hours, or 3-5 hours.

In one embodiment, the mixed solution is for use in a method fortreating a subject in pain, wherein the method comprises mixing apharmaceutical solution of meloxicam with a pharmaceutical solution ofan amide-type local anesthetic to prepare a mixed solution, andadministering the mixed solution to the subject within 24 hours ofpreparing the mixed solution. The method may also compriseprophylactically treating a subject for pain.

Compositions were prepared and tested in support of the presentcompositions and methods of use, now described with reference toExamples 1-8. Each of the illustrative compositions described inExamples 1-8 comprises a polyorthoester (POE) of Formula I comprised of80% triethylene glycol (TEG) and 20% TEG-glycolide (comprising onaverage 2 glycolides per subunit, i.e., TEG-diglycolide). See, e.g.,U.S. Pat. No. 8,252,305, Example 1(d). Compositions containing between45% to 80% polyorthoester of Formula I, between 20% and 45% of anaprotic solvent, 5% ropivacaine, and 3.6% meloxicam were prepared asdescribed in Example 1. The composition identified in Example 1 as8026-01-01 was comprised of 61.5 wt % polyorthoester of Formula I, 29.7wt % of the aprotic solvent NMP, 5.2 wt % ropivacaine base and 3.6%meloxicam. Release rates of ropivacaine and meloxicam were measured invitro, according to the in vitro test described in Example 2, where aknown amount of the composition was placed in a known amount ofphosphate buffered saline in a vial. The vial containing the saline andpolymeric composition was incubated at 37° C. without agitation, andaliquots of the saline were removed and fixed time intervals. Theconcentration of each drug was measured in the aliquots. The cumulativedrug release from the polymeric depot composition is shown in Table 2-1of Example 2 and shows that 100% release of both drugs was attained by72 hours (3 days).

Accordingly, in one embodiment, a composition comprised of apolyorthoester, an amide-type anesthetic and an enolic-acid NSAID iscontemplated, where the anesthetic and NSAID are released in vitro fromthe composition over a period of between about 1-3 days, or over aperiod of at least about 2 days, or over a period of at least about 3days.

In another study, described in Example 3, compositions containingbetween approximately 62-63% polyorthoester of Formula I, betweenapproximately 15-20% of an aprotic solvent, between 10% and 15%bupivacaine base, and 6% to 7.5% diclofenac were prepared.

In another study, described in Example 4, compositions containingbetween approximately 55% to 80% polyorthoester of Formula I, betweenapproximately 15% and 35% of an aprotic solvent, between about 5-15 wt %bupivacaine, and between about 0.05-3.5 wt % meloxicam were prepared andthe in vitro release rates of bupivacaine and meloxicam was measured.The test for measuring in vitro release rates is described in Example 5,and Tables 5-1 and -5-2 in the example summarize the cumulative percentrelease of each drug from the compositions. The compositions comprisingbetween 55-65 wt % POE and 16-32 wt % of an aprotic solvent provided anextended period of release of bupivacaine with between 37-75 percent ofthe drug released after 168 hours in vitro. Compositions comprising70-80 wt % POE, 15 wt % of an aprotic solvent, and 0.5-1.2 wt % of anorganic acid (maleic acid) provided a faster rate of drug release, withsubstantially all drug (e.g., over about 80%, 85% or 90% of thebupivacaine load) released in about 120 hours. This study shows how theaddition of optional excipients, such as the organic acid, can tailorthe period of drug release in the compositions.

Several of the compositions prepared in Example 4 were tested in vivo tomeasure the pharmacokinetics of bupivacaine and meloxicam. Thecompositions identified in Table 4-1 (Example 4) as 8026-04-03,8026-04-04 and 8026-04-05 were injected with 4 mL of a composition, andplasma concentration of the drugs was determined from blood samplestaken for up to 7 days after administration (see Example 6). The datafrom the study is shown in FIGS. 1A-1B, where plasma levels ofbupivacaine (FIG. 1A) and of meloxicam (FIG. 1B) are plotted at eachtime point, for the three compositions—15 wt % bupivacaine/3 wt %meloxicam (closed squares; composition no. 8026-04-03); 10 wt %bupivacaine/0.75 wt % meloxicam (open circles; composition no.8026-04-04); and 5 wt % bupivacaine/0.38 wt % meloxicam (open triangles;composition no. 8026-04-05). The data indicates that the compositionsprovide measurable plasma concentrations of bupivacaine and meloxicamover a period of at least about 4 days (96 hours) or at least about 3days, following administration.

Another in vivo pharmacokinetic study was conducted in dogs, asdescribed in Example 7. The composition comprised of 79% polyorthoester,0.6 wt % maleic acid, 15 wt % NMP, 5% bupivacaine and 0.15 wt %meloxicam (composition identification no. 8026-04-07, Example 4) wasadministered in two separate injections of approximately 0.5 mL each.Plasma samples were collected from each dog and were analyzed forbupivacaine and meloxicam. The data from the study is shown in FIGS. 2Aand 2B.

FIGS. 2A-2B are graphs of plasma concentration of bupivacaine (FIG. 2A)and of meloxicam (FIG. 2B), in ng/mL, as a function of time, in hours,after administration in vivo to a dog of a composition (no. 8026-04-07)comprised of a polyorthoester delivery vehicle and 5 wt % bupivacaineand 0.15 wt % meloxicam The composition provides measurable plasmaconcentrations of bupivacaine and meloxicam over a period of at least 4days (96 hours) or at least about 3 days, following administration.

Example 8 describes several studies conducted to evaluate thepharmacodynamics of the bupivacaine-meloxicam compositions. Using apost-operative (POP) pain porcine model system, where a 7 cm long skinand fascia incision was made in the left flank under general anesthesiato pigs, the test composition or control article was applied to thewound. The skin incision was then closed using sterile sutures.Post-operative pain was assessed using the Von Frey methodology, asdescribed in Example 8. In a first study (Example 8A), extended releasepolymer composition containing 15% bupivacaine was compared to anextended release polymer composition containing 5% ropivacaine. Themethod of administration to the surgical site was varied to evaluatewhether this resulted in any difference in pharmacodynamics. The methodstested were to either instill the composition directly onto the surfaceof the wound area or inject the composition subcutaneously into thelateral margins of the wound. Table 8-1 details the test groups andmethod of administration.

The pharmacodynamic response, measured by the von Frey test, is shown inFIG. 3. Withdrawal force, in gram force, is shown as a function of time,in hours and days, after administration in vivo for each of thefollowing compositions: compositions comprised of a polyorthoesterdelivery vehicle and either (i) 15 wt % bupivacaine administered byinjection (vertical dashes fill; Group 2) or by instillation (verticalline fill; Group 3) or (ii) 5 wt % ropivacaine administered by injection(horizontal line fill; Group 4) or instillation (diamond crosshatchfill; Group 5); bars with dotted fill represent the response for thecontrol group treated with saline (Group 1). Subcutaneous injection ofcompositions comprising ropivacaine or bupivacaine both offered asustained effect following a single administration prior to woundclosure. Application of the composition onto the wound surface was lesseffective than injection for the 15% bupivacaine composition; however acorresponding difference between modes of administration was notobserved with the 5% ropivacaine composition. Comparing Groups 2 and 4,there was a significant increase in force required to provoke withdrawalon Days 0 and 2 through 5 in the pigs administered either composition bywound injection compared to the vehicle controls. There was littledifference in response between bupivacaine and ropivacaine compositionsand an increase in sensitivity (lower force to provoke a withdrawal) wasobserved in all drug treatment groups on Days 2-4 with some increase inthe force required to provoke a withdrawal in pigs that received drugtreatment (Groups 2-5) on Day 6. It was hypothesized thatinflammation-mediated failure of the local anesthetic was the reason forthe diminished effectiveness on Days 2-4 and recovery on Day 6 asinflammation subsided.

Another pharmacodynamics study was conducted (Example 8B) to compare theefficacy of extended release formulations containing a local anestheticto formulations containing a local anesthetic in combination with anNSAID. The nociceptive activity of five different formulationssummarized in Table 8-2 of Example 8B was evaluated in the pig POPmodel. Extended release formulations containing ropivacaine (slowerrelease and faster release, Groups 2 and 3 respectively) were comparedto extended release formulations containing bupivacaine and the NSAIDsdiclofenac and meloxicam, Groups 4 and 5 respectively. A dose volume of2 mL for vehicle or test article was injected subcutaneously into thelateral margins of the incision and the incision closed with sutures.Assessment of nociception by von Frey method at baseline, 1, 3, and 5hours, and days 1 through 6 after surgery.

The results are shown in FIG. 4, where withdrawal force, in gram force,is shown as a function of time, in hours and days, after administration.The compositions are denoted in FIG. 4 as follows: compositionscomprised of a polyorthoester delivery vehicle and (i) 5 wt %ropivacaine with 0.6% maleic acid (horizontal line fill; Group 2), (ii)5 wt % ropivacaine with 0.2% maleic acid (diamond crosshatch fill; Group3), (iii) 15 wt % bupivacaine and 7.5 wt % diclofenac (vertical dashesfill; Group 4), or (iv) 15 wt % bupivacaine and 3.5 wt % meloxicam(vertical line fill; Group 5); and bars with dotted fill represent theresponse for the control group treated with saline (Group 1).

The results indicate that, with the exception of the control, all of thecompositions evaluated in the model were effective in the short-term fortreatment/management of pain, e.g., in the first 5 hours post-incision.The extended release polymer composition containing ropivacaine as theonly active agent (Group 3) was as effective in the first 5 hours afteradministration as the extended release polymer composition comprisingbupivacaine in combination with meloxicam and bupivacaine combined withdiclofenac. At the 5 hour time point, the composition comprisingropivacaine alone tested in Group 1, but with a higher amount of maleicacid than the composition tested in Group 2, was less effective in itsrelief of pain, as can be seen in the reduced withdrawal force recordedin comparison with the other three compositions. This is likely due tothe higher content of maleic acid in the composition, thereby leading toa faster release rate of the active agent (see, e.g., U.S. PatentApplication No. 61/982,300, filed Apr. 21, 2014). A notable differencein the compositions is observed at the longer time points, e.g., overdays 1-6. Over days 1-3, compositions containing ropivacaine alone (inreference to the active agent), as well as the bupivacaine/diclofenaccomposition, exhibited diminishing analgesia, as shown by a trend inreduced withdrawal force. In contrast, the composition comprising thecombination of bupivacaine and meloxicam was significantly moreeffective than the other three compositions. The analgesia achieved bythe composition comprising the combination of bupivacaine and meloxicamremained essentially unchanged over the course of the entire study andthe measured withdrawal force exhibited for this composition was, withthe exception of day 1, the maximum measured force. While late in thestudy, the compositions containing ropivacaine alone (Groups 2 and 3)appeared to regain their analgesic effect, as demonstrated by theincreased withdrawal force observed over days 4-6, neither was aseffective or as consistent in its pain reduction as thebupivacaine/meloxicam composition, which maintained its analgesicactivity over days 1-6. In contrast to the bupivacaine/meloxicamcomposition, the bupivacaine composition containing a different NSAID,diclofenac, continued to diminish in its ability to provide pain reliefover time, as illustrated by a trend in decreasing withdrawal force fromabout 5 hours to about 6 days.

Thus, the two compositions containing different NSAIDs exhibiteddifferent pain relief profiles in the post-operative pain modelemployed. The data unexpectedly shows that incorporation of anenolic-acid NSAID (such as meloxicam) into the composition allowed thelocal “caine”-type anesthetic to better function and provide analgesia.The pain response profile for the bupivacaine/meloxicam combinationillustrates good short term efficacy, over about the first 1-10 hours orso post-surgery, followed by a small drop in efficacy on day 1, and asubsequent rapid recovery such that by about day 2, the composition isagain effective in providing maximal pain relief from day 2 to at leastday 6 as evidenced by the plateau in withdrawal force observed. Thecombination is notably superior over the other compositions tested, andin the present study, provides surprisingly enhanced pain relief,especially in comparison to the bupivacaine/diclofenac composition.

Another pharmcodynamic study was conducted to evaluate five differentformulations containing different concentrations of the two activeingredients, bupivacaine and meloxicam. As described in Example 8C, theformulation summarized in Table 8-3 were administered either by 1)subcutaneous injection around the wound margins or 2) by directapplication to the wound surface created by the incision or 3) injectedinto the tissues on either side of the wound. The results showed thatall bupivacaine/meloxicam compositions demonstrated good analgesiathrough day 6 post-administration (data not shown) consistent with theprevious study (Example 8B). The data also suggested that a bupivacaineconcentration of greater than about 5 wt % in the composition offers noadditional analgesia. A dose response for meloxicam was not observed.Thus, in one embodiment, compositions comprising an amide-type localanesthetic is between about 0.01-7.5 wt %, alternatively between about0.1-6 wt %, alternatively between about 0.5-5 wt %.

Example 8D describes another study conducted to evaluate the in vivoresponse provided by compositions containing 5 wt % bupivacaine withvarying concentrations of meloxicam ranging from 0.08 to 0.3 wt %. Table8-4 summarizes the compositions and test groups. The compositions wereadministered to pigs as subcutaneous injections into both sides of theincision, and analgesia was evaluated using the von Frey test.

Results are shown in FIGS. 5A-5B, where withdrawal force, in gram force,is shown as a function of time, in hours and days, after administration.The test compositions are denoted in FIGS. 5A-5B as follows: comprisedof a polyorthoester delivery vehicle and 5 wt % bupivacaine incombination with meloxicam at 0.08 wt % (vertical dash fill; Group 2),0.19 wt % meloxicam (vertical line fill; Group 1), and 0.3 wt %meloxicam (horizontal line fill; Group 3), a composition comprised of apolyorthoester delivery vehicle and 0.15 wt % meloxicam alone (dottedfil: Group 4) (FIG. 5A) and compositions comprised of a polyorthoesterdelivery vehicle and 5 wt % ropivacaine in combination with 0.38 wt %meloxicam (diamond crosshatch fill; Group 5) or with 5 wt % ropivacainealone (no fill; open bars; Group 6). A variable degrees ofanti-nociception were obtained across the 6-day post-surgeryobservations for Groups 1, 2 and 3 with diminishing analgesia observedin the Group 2 composition containing 0.08% meloxicam. The Group 4composition of meloxicam alone showed essentially no analgesic effect.The formulations containing ropivacaine with and without meloxicamdemonstrated the same trend as seen with bupivacaine formulations (seeFIG. 5B). Meloxicam had a positive anti-nociceptive contribution to theeffect beyond the effect seen with the local anesthetic alone. The dataalso suggests that between about 0.01-5 wt % amide-type local anestheticin combination with at least about 0.1 wt % or 0.15 wt % of anenolic-acid NSAID provides a synergistic effect in analgesia.

Accordingly, as evidenced by the data in FIG. 4 and FIGS. 5A-5B, in oneembodiment, the compositions are administered for the management ofpain, for the treatment of pain, or for prophylactic treatment of pain,to a person in need. Administration provides, as measured in an in vivomodel for post-operative pain, a decrease in pain relief afteradministering, where the decrease in pain relief is for a periodmeasured from about one (1) hour and about 3-8 hours or about 3-24 hoursafter administering and is relative to the pain relief measured at timesless than one hour after administration (e.g., at baseline with regardto FIG. 4). The period of decreased pain relief is followed by a periodof increased or increasing pain relief, where this period is frombetween about 1-3 days or about 1-4 days or about 1-5 days afteradministering. The increased or increasing pain relief during the periodof increased pain relief is with respect to the pain relief measuredduring the period of decreased pain relief. In one embodiment, the painrelief during the period of decreased pain relief and/or during theperiod of increased pain relief is an average of the values measured inthe in vivo model for post-operative pain during the relevant period. Inanother embodiment, the pain relief during the period of increased painrelief is considered an increased pain relief if the pain reliefmeasured in the in vivo model for post-operative pain is greater on day2 than on day 1 (24 hours) after administration. In another embodiment,the pain relief during the period of increased pain relief is consideredan increased pain relief if the pain relief measured in the in vivomodel for post-operative pain is greater on day 3 than on day 1 (24hours) after administration. In another embodiment, the pain reliefduring the period of increased pain relief is considered an increasedpain relief if the pain relief measured at any time point in the periodusing an in vivo model for post-operative pain is within about 10% ofthe pain relief at any time point measured in the in vivo model forpost-operative pain at times less than 1 hour after administration(e.g., baseline).

In another embodiment, the composition provides pain relief (as measuredin an in vivo model for post-operative pain) over a period of betweenabout 2-5 days following administration that is at least, on average,about 50% of the average pain relief provided by the composition 1-5hours post-administration. The average pain relief during a time period,e.g., during a time period of 1-5 hours post-administration, in oneembodiment, is the average of the pain relief scores or values collectedduring the time period. In one embodiment, average refers to thearithmetic mean, where the average pain relief is obtained bycalculating the sum of the pain relief scores or values during a timeperiod and dividing that sum by the number of summed values or scores.

2. Compositions Comprising a Viscosity Reducing Triglyceride Solvent

With respect to the compositions described herein which comprise abiodegradable polyorthoester polymer as the delivery vehicle, thesecompositions find use, for example, as drug delivery systems or asmedical or surgical devices. For such uses, the composition is typicallyadministered by injection into the body with standard syringes and smallgauge needles. Thus, it is desirable to provide a composition with aviscosity that is readily dispensed from syringes and small gaugeneedles yet has the release kinetics of active agent required fortherapy. As is known in the art, for example in U.S. Patent PublicationNo. US2014/0275145, which is incorporated herein by reference in itsentirety, the selection of an aprotic polar solvent or solvents in thesystem may be used to modulate the release profile of an active agentfrom the polymeric composition. These compositions comprising a polaraprotic solvent and a polyorthoester have viscosities of less than about10,000 mPa-s at 37° C., and a drug release profile that depends on thesolvent choice and amount. Provided herein are compositions with aviscosity suitable for administration via a needle to a subject in need,with a drug release profile similar to a composition with a higherviscosity. As will be illustrated, these compositions find use inapplications that require injection through long narrow gauge needles,as in use as a nerve block, or in forming depots in situ for long-termdelivery of active agents, such as granisetron for managing nausea.

As can be appreciated, the viscosity of a composition is temperaturedependent. For example, a composition with a viscosity of 10,000 mPa-smeasured at 37° C. will have a higher viscosity measured at 25° C.; andfor the polyorthoester compositions described herein, the viscosity at25° C. is often from about 7 to 10 fold higher than the viscosity at 37°C. Because the compositions are generally stored at room temperature andadministered at room temperature (20-25° C.) it is desirable to havecompositions wherein the viscosity is such that the composition can bereadily administered at 25° C. through a needle. This embodiment of theinvention provides such a composition.

It was found that a triglyceride solvent can be added to compositionscomprising a polyorthoester and a polar aprotic solvent to provide a 10,20, 30 or 40-fold reduction in composition viscosity when measured at25° C. with a viscometer (relative to viscosity of a similar compositionlacking the triglyceride solvent measured at 25° C. with a viscometer)without significantly altering the drug release kinetic as reflected inthe in vitro release profile or in the pharmacokinetic profile of thecomposition. Such is not the case with polar aprotic solvents, where theamount of solvent in a composition will have a measurable impact on thedrug release kinetics. That is, by way of example, an initialcomposition containing a certain concentration of a polar aproticsolvent will demonstrate specific drug release kinetics. Increasing theconcentration of that polar aprotic solvent by adding more of that polaraprotic solvent to the initial composition will typically result in anew composition with altered drug release kinetics relative to theinitial composition. Surprisingly, this is not the case when atriglyceride viscosity reducing agent is added to compositionscontaining polar aprotic solvents. Beneficially, the viscosity of acomposition may be reduced by a factor of 10, 12, 15, 20, 30 or 40 bythe addition of a triglyceride viscosity reducing agent to a compositioncomprising a polyorthoester and a polar aprotic solvent with minimalalteration of the drug release profile as compared to a similarcomposition lacking the triglyceride viscosity reducing agent. Thetriglyceride viscosity reducing agent is one having three fatty acidgroups wherein each fatty acid group independently has between 1-7carbon atoms, and is referred to in some cases as a ‘short chaintriglyceride.’ In some embodiments, the delivery system has a viscosityof less than about 10,000 mPa-s, 5,000 mPa-s, or 2,500 mPa-s, whenmeasured at 25° C. using a viscometer.

Exemplary triglyceride viscosity reducing agents include but are notlimited to triacetin (1,2,3-triacetoxypropane, 1,2,3-triacetylglycerol,glycerol triacetate, or glyceryl triacetate); tripropionin (glyceryltripropionate or 1,2,3-triproprylglycerol); or tributyrin(1,2,3-tributyrylglycerol, or glycerol tributyrate). These triglycerideviscosity reducing agents have three fatty acid chains, wherein eachfatty acid chain independently has between 1-7 carbons, and is thus arelatively ‘short chain’ fatty acid ester. It is understood thatcombinations of short chain esters are also acceptable, for exampleglycerol diacetate monopropionate and the like.

The aprotic solvent is a solvent with a dipole moment of greater thanabout 2 debye (D) (6.67×10⁻³⁰ coulomb meter), or greater than about 2.2D (7.34×10⁻³⁰ coulomb meter), or greater than about 2.4 D (8.05×10⁻³⁰coulomb meter). In one embodiment, the aprotic solvent is a solvent witha dipole moment of greater than about 2 D, or greater than about 2.2 D,or greater than about 2.4 D and is water miscible. In anotherembodiment, the aprotic solvent is a solvent with a dipole moment ofgreater than about 2 D, or greater than about 2.2 D, or greater thanabout 2.4 D and is poorly miscible in water. In one embodiment, asolvent is miscible with water if it forms a homogeneous solution withwater in all proportions at room temperature (20-25° C.). A solvent ispartially miscible if it forms a homogeneous solution with water in someproportions at room temperature (20-25° C.). A solvent is poorlymiscible if it does not form a homogeneous solution with water (20-25°C.). Examples of aprotic solvents suitable for use in the deliverysystems are described, for example, in U.S. Pat. Pub. No. 2014/0275046(incorporated herein by reference in its entirety), however, exemplaryaprotic solvents may encompass amides, ethers, ketones, or sulfoxides.Exemplary amides include 2-pyrrolidone, dimethyl formamide,N-methyl-2-pyrrolidone and dimethyl acetamide. Exemplary ethers includedimethyl isosorbide and tetrahydrofuran. Exemplary ketones includeacetone and methyl ethyl ketone. Exemplary sulfoxides include dimethylsulfoxide and decylmethylsulfoxide. Additional polar aprotic solventssuitable for use in these low viscosity delivery systems includelactones such as ester-caprolactone and butyrolactone and esters such asan alcohol, propylene carbonate (4-methyl-1,3-diololan-2-one).

In such a delivery system which comprises a polyorthoester, such as thatdescribed herein as Formula I, II, III or IV, a polar aprotic solventand a triglyceride viscosity reducing agent, the polyorthoester ismiscible within the solvent comprising the triglyceride viscosityreducing agent and polar aprotic solvent. Accordingly, the compositioncan be prepared to form a single phase into which a therapeuticallyactive agent is dispersed or solubilized for efficient delivery.

In a particular embodiment, the delivery system comprises apolyorthoester described herein as Formula I, the short chaintriglyceride viscosity reducing agent triacetin, and a polar aproticsolvent which is dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) ordimethyl acetamide (DMAC).

Pharmaceutical delivery systems comprising the polyorthoester,triglyceride viscosity reducing agent and polar aprotic solvent can beused as delivery systems for administration of any therapeuticallyactive agent to provide delivery of the agent over a desired period oftime. The therapeutic agent is one which can be dispersed or solubilizedin the single phase which is formed by the combination of thepolyorthoester, short chain triglyceride viscosity reducing agent andpolar aprotic solvent.

Methods for making the delivery systems described above may be achievedby a process as described in Examples 10 and 14. In one embodiment, anactive agent is dissolved in an aprotic solvent. The dissolution may beperformed at an elevated temperature such as from about 60-80° C. or atabout 80° C. Separately, appropriate amounts of polyorthoester polymerand short chain triglyceride viscosity reducing agent are combined andmixed thoroughly. The polyorthoester polymer and short chaintriglyceride viscosity reducing agent can be combined and/or mixed at anelevated temperature of between about 60-80° C. or between about 65-75°C. or at about 7o ° C. The solution containing the active agent is thencombined with the appropriate amount of the blend of polymer and shortchain triglyceride and mixed until homogeneous. It has been observedthat the presence of the triglyceride viscosity reducing agent canreduce the viscosity of the delivery system by about 10 to 40-fold ascompared to the delivery system in the absence of the triglycerideviscosity reducing agent. Such delivery systems are referred to hereinas “low viscosity delivery systems.” The low viscosity delivery systemsprovide the duration and level of relief (e.g., relief from nausea orrelief from pain) similar to that observed after administration of asimilar composition formulated without the triglyceride viscosityreducing agent.

Low viscosity delivery systems can be formulated with appropriateamounts of the polyorthoester, solvent comprising a short chaintriglyceride viscosity reducing agent and polar aprotic solvent. Forexample, a low viscosity delivery system may be formulated to contain40% to 75%, 40% to 60%, 45% to 55%, 65 to 75%, or about 40%, 45%, 50%,55%, 60%, 65%, 70%, or 75% by weight of the polyorthoester. The polaraprotic solvent in the delivery system may be present in a weightpercent ranging from about 3% to 25%, 3% to 10%, 5% to 7.5%, 10% to 25%,15% to 20%, or about 3%, 5%, 7.5%, 10%, 12%, 15%, 20%, or 25%. Thesolvent comprising the short chain triglyceride viscosity reducing agentis in the composition at a weight percent of about 5% to 45%, 30% to45%, 35% to 40%, 5% to 25%, 10% to 20%, or about 5%, 10%, 15%, 20%, 25%,30%, 35% or 40%.

The low viscosity delivery system can contain more than one activeagent. In some embodiments, the one or more active agents must besoluble in the solvent comprising the short chain triglyceride viscosityreducing agent, in the polar aprotic solvent or in a mixture of the twosolvents. The active agent(s) is dispersed in or solubilized in thedelivery system containing the polyorthoester. The total weight percentof active agent in the low viscosity delivery system can vary, forexample, from about 0.1% to 5%, 0.1% to 10%, 0.1% to 5%, 2.5% to 7.5%,3% to 5%, or at about 0.1%, 0.25%, 0.5%, 1.0%, 2.5%, 5%, 7.5% or 10% byweight.

Studies conducted in support of this aspect of the invention as setforth in Examples 9-13, now to be described. In each of these examples,compositions using a delivery vehicle comprised of a polyorthoester(POE) of Formula I comprising 80% triethylene glycol (TEG) and 20%TEG-glycolide (comprising on average 2 glycolides per subunit, i.e.,TEG-diglycolide) was used. See, e.g., U.S. Pat. No. 8,252,305, Example1(d).

In a first study, described in Example 9, a composition prepared asdescribed in Example 4 (composition identification no. 8026-04-07) wasprepared and a similar composition with 30% triacetin (glyceroltriacetate) as a model triglyceride viscosity reducing agent wasprepared. The viscosity of the composition with the triglycerideviscosity reducing agent was measured using a viscometer at 25° C. andwas at 7,115 mPa-s.

The composition with the triglyceride viscosity reducing agent wascompared to the composition with no triglyceride viscosity reducingagent in a canine pharmacokinetic study, as described in Example 10.Dogs received two separate injections of a test composition, and bloodsamples were collected from each dog at the predetermined time points.The blood samples were subsequently analyzed for bupivacaine andmeloxicam plasma concentrations. The data is shown in FIGS. 6A-6B. Thedata indicates that the compositions provide very similar plasma PKprofiles with only a small increase in Cmax for the compositioncomprising a triglyceride viscosity reducing agent (open circles) inrelation to the composition lacking the triglyceride viscosity reducingagent (triangles).

FIGS. 6A and 6B are graphs demonstrating very similar plasmaconcentration curves for bupivacaine and meloxicam, respectively, fortwo illustrative compositions described in Example 9. The illustrativecompositions: 8026-04-07 (5.0 wt % bupivacaine, 0.15 wt % meloxicam,79.3 wt % polyorthoester, 0.6 wt % maleic acid and 15% N-methylpyrrolidone [aprotic solvent]) and 8026-09-01 (3.84 wt % bupivacaine,0.11 wt % meloxicam, 60.96 wt % polyorthoester, 0.46 wt % maleic acid,23.08 wt % triacetin, and 11.5 wt % N-methyl pyrrolidone [aproticsolvent]). In these particular compositions, the viscosity of theundiluted composition (8026-04-07) is approximately 70,000 mPa-s at 25°C. while the viscosity of the triacetin containing composition isapproximately 7,000 mPa-s at 25° C. The plasma concentration curves forbupivacaine and meloxicam indicate that, with the exception of aslightly higher Cmax, the plasma concentrations curves for the triacetindiluted composition, 8026-09-01, is nearly identical to the plasmaconcentration curves for the undiluted composition, 8026-04-07. Whilethese investigations demonstrate that compositions can be formulatedwith triacetin to yield compositions with reduced viscosity with onlymodest changes in the drug release kinetics, it is recognizedcompositions can be further optimized with respect to viscosity and drugrelease kinetics by further adjustments to the composition, such as bymodulation of the concentration of polar aprotic solvent, triacetin orother components of the composition.

In another study, described in Example 10, delivery systems comprising acombination of an amide-type local anesthetic and an enolic-acid NSAIDwith a triglyceride viscosity reducing agent were prepared. Thecompositions are summarized in Table 10-1 in Example 10. The viscosityof the compositions was measured (according to the procedure in theMethods section of the Examples), and is shown in Table 10-1. Theaddition of triglyceride viscosity reducing agent to the compositionsdecreased the viscosity at least 10-fold, at least 20-fold, or at least40-fold, or more, as compared to compositions lacking the triglycerideviscosity reducing agent.

The in vitro release of bupivacaine and meloxicam from the compositionsof Table 10-1 was measured in the test described in Example 11. Tables11-1 and 11-2 in Example 11 shows the cumulative percent release ofbupivacaine and meloxicam, respectively, from the compositions. Thecompositions provided an in vitro release of both drugs over an extendedtime period of 3 days or more.

An in vivo pharmacokinetic study was conducted to evaluate the releaseof drug from delivery systems comprising bupivacaine and meloxicam and atriglyceride viscosity reducing agent. As described in Example 12, dogswere treated with 2 mLs of the composition identification nos.8026-10-03 and 8026-10-05 (Example 10, Table 10-1) in two separateinjections. Blood samples were taken and the plasma analyzed forbupivacaine and meloxicam concentrations. The data from the study isshown in FIGS. 7A-7B. The compositions provided measurable plasmaconcentrations of bupivacaine (FIG. 7A) and meloxicam (FIG. 7B) over aperiod of at least 96 hours following administration, where thecomposition with 35 wt % triacetin (8026-10-03) is indicated by thetriangles and the composition with 30 wt % triacetin (8026-10-05) isrepresented by the open circles.

The reduced viscosity of the compositions comprising a triglycerideviscosity reducing agent and no significant alteration of kineticrelease of drug from the composition, relative to a similar compositionlacking the triglyceride viscosity reducing agent, provides anopportunity for use of the compositions in clinical settings where thecomposition is injected via needle, as in a nerve block. Accordingly, astudy was conducted to evaluate use of the compositions as a nerveblock. As described in Example 13, four grams of each composition setforth in Table 13-1 were injected into each of 4 animals andadministered so as to be near the sciatic nerve in one flank of the pig.To assess the degree of nerve block, Von Frey filaments (Ugo Basile)were applied at the dorsal source surface of the foot as described inExample 13. The results of the Von Frey assay are presented in FIG. 8.

FIG. 8 is a bar graph of withdrawal force, in gram force, as a functionof time, in hours and days, after administration in vivo to pigs ofcompositions comprised of a polyorthoester delivery vehicle, 2.5 wt %bupivacaine alone (Group 4, 8026-13-01, vertical dashes fill) or 2.5 wt% bupivacaine, 0.0175 wt % meloxicam and 0.15% maleic acid (Group 3,8026-10-01, vertical line fill) or 0.10 wt % maleic acid (Group 5,8026-0-02, horizontal line fill), or a buffered solution of 0.5 wt %bupivacaine (no fill; open bars, Group 2); bars with dotted fillrepresent the response for the control group treated with saline. Thedata shows that animals administered a composition comprising bothbupivacaine and meloxicam had a higher threshold for responding topressure. The efficacy of the combination compositions containing bothbupivacaine and meloxicam were longer lasting and provided deeperanesthesia than did a similar composition containing bupivacaine butwithout meloxicam.

The data in FIG. 8 shows the effectiveness of several compositions as anerve block using the in vivo porcine model. The lower viscosity polymerdelivery compositions comprising bupivacaine and meloxicam, whenadministered as a nerve block, maintained the advantage of thebupivacaine and meloxicam combination to provide longer lasting anddeeper anesthesia as compared to bupivacaine in the absence ofmeloxicam. The polyorthoester compositions having low viscosities, suchas a viscosity between 2000 mPa-s and 4000 mPa-s, measured at 25 C usinga viscometer, were surprisingly effective as a nerve block. One mightexpect the lower viscosity to result in a drug release rate too rapidfor effective extended release, but the data show otherwise.

It will be appreciated that the use of a triglyceride viscosity reducingagent can be utilized in a polyorthoester delivery system for a varietyof therapeutic agents. An illustrative example is provided in Example14, where a delivery system comprising a polyorthoester polymer, a shortchain triglyceride viscosity reducing agent, and a polar aprotic solventand an anti-emetic therapeutic agent was prepared. In one embodiment,the anti-emetic is used to treat emesis induced by a chemotherapeuticagent, by radiation-induced nausea and vomiting, and/or bypost-operative induced nausea and vomiting in a patient. The treatmentincludes administering to the patient the composition comprising ananti-emetic, such as a 5-HT3 antagonist, where the composition isdesigned to yield a rate of release for effective anti-emetic therapy.In an exemplary embodiment, the anti-emetic is granisetron. The deliverysystem can be administered, e.g., intravenously. As seen in the datapresented in Table 14-1 of Example 14, the addition of the triglycerideviscosity reducing agent triacetin to the compositions decreased theviscosity between about 5-fold and 90-fold as compared to compositionslacking a triglyceride viscosity reducing agent. The reduction inviscosity, when viscosity is measured at 25° C. using a viscometer (seethe Method set forth below), in one embodiment, is at least about 5fold, at least about 7-fold, at least about 20 fold, at least about 30fold, at least about 40 fold, at least about 50 fold, at least about60-fold, at least about 70-fold, at least about 80-fold or at leastabout 90-fold. The addition of a triglyceride viscosity reducing agentto the compositions decreased the viscosity, when measured at 37° C.using a viscometer, by at least about 5 fold or by at least about10-fold, or by at least about 20-fold, or by at least about 30-fold.

The in vitro release of granisetron from the compositions of Example 14was determined as described in Example 15. Cumulative drug release issummarized in Table 15-1 of Example 15 and shows that release of thedrug is comparable with the drug release profile across compositionswith and without varying triacetin concentrations. There was an increasein the in vitro release rate when the concentration of polar aproticsolvent was increased. Decreasing the viscosity by increasing the amountof polar aprotic solvent increased the drug release by about 2-fold.However, the same increase in triacetin concentration did not cause thesame increase in rate of release. Additionally, the compositionsprovided release of granisetron for at least about 3 days or at leastabout 4 days. The addition of a triglyceride viscosity reducing agent toreduce viscosity of the compositions did not alter the in vitro releaseof granisetron relative to a similar composition lacking the atriglyceride viscosity reducing agent. This is seen in the data of Table15-1 by comparing composition number 8026-14-03, with no triacetin, and8026-14-04, with 10% triacetin. Release of granisetron from thetriacetin composition (which had a nearly 20-fold lower viscosity at 25°C.) was within 10% of the granisetron cumulative release provided by asimilar composition lacking the triacetin. Similarly, a comparison of8026-14-01 (with no triacetin) and 8026-14-02 (with 10 wt % triacetin)reveals that the triacetin-containing composition with a 7-fold lowerviscosity at 25° C. released granisetron at a rate within about 15% ofthe release provided by the composition with no triacetin at the 24hour, 72 hour and 96 hour time points. Accordingly, in one embodiment,compositions with a triglyceride viscosity reducing agent have aviscosity that is at least about 5-fold or 10-fold (or more, as notedabove) when viscosity is measured at 25° C. using a viscometer, and arelease of active agent that is within about 20%, 15% or 10% of therelease of agent from a similar composition lacking the triglycerideviscosity reducing agent at least one time point, at least two timepoints or at least three time points during a 96 hour period.

The reduced viscosity compositions as described above are suitable foradministering to a subject in need thereof. For example, a low viscositycomposition containing a therapeutically effective amount of the one ormore active agents can be administered subcutaneously, intradermally orintramuscularly to a subject in need of the active agent(s), or appliedtopically or instilled into tissue or, e.g., a wound (surgical orotherwise).

The low viscosity compositions and systems comprising a triglycerideviscosity reducing agent such as triacetin, as disclosed herein, areadministered to a subject (e.g., patient) in need of treatment for orprevention of a condition, in an effective amount of the flowablecomposition described herein. These low viscosity compositions providethe advantages of liquid delivery systems for active agents with thedelivery profile of viscous polymer or solid polymer delivery systems.The present low viscosity compositions comprising a triglycerideviscosity reducing agent such as triacetin also enable the use ofsmaller gauge needles compared to other liquid polymer systems. The useof biodegradable polymers in the present compositions comprising atriglyceride viscosity reducing agent, such as triacetin, also allowsthe rate of release of an active agent and degradation of the flowablecomposition to be varied over a wide range in contrast to thenon-polymeric flowable compositions.

Each composition as disclosed herein comprising a polymer such as apolyorthoester can be characterized in terms of release of the activeagent(s) dissolved or dispersed within it. For example, release of oneor more drugs from the composition can be determined by placing a smallamount of each polymer formulation (e.g., 50 to 500 mg) into a volume ofbuffer (e.g., 150 mL phosphate buffered saline in an appropriatecontainer). The sample is then incubated at, for example, 25° C., 37° C.or 50° C., with or without agitation. At intervals of time, e.g., every6 hours, 12 hours, or 24 hours, aliquots of the buffer solution areremoved and analyzed for the presence of active agent. Analysis can beperformed by, for example, high performance liquid chromatography.

B. Methods of Treatment

The compositions provided can be used, for example, in managing pain ina patient. Accordingly, methods of ameliorating pain, managing pain,treating pain and/or providing local anesthesia to a patient in needthereof are provided. In another embodiment, a method for theprophylactic treatment of pain is provided, such as in the situation ofmanaging or treating post-operative pain. In other embodiments, providedis a method for extending the pain-relief profile of a polyorthoestercomposition comprising an the amide- or anilide-type local anesthetic byincorporating therein, an efficacy-enhancing amount of an enolic-acidNSAID such as meloxicam, to thereby provide a composition capable ofproviding effective pain relief for a period of time that is extendedover that of the same composition absent the NSAID. In particular, thecomposition comprising a combination of an amide-type anesthetic and anenolic-acid NSAID is effective to provide pain relief from about 1 dayto at least about 2 days or at least about 3 days or at least about 4days or at least about 5 days following administration, i.e., is along-acting composition for pain relief, rather than a short-actingcomposition. In other embodiments, the composition provides relief ofpain for a period of up to about 4 days or up to about 5 days.

In yet an additional aspect, provided is a method for altering theanalgesic or pain relief effect of a polyorthoester compositioncomprising an the amide-type local anesthetic by incorporating therein,an efficacy-enhancing amount of an enolic-acid NSAID, to thereby providea composition having an analgesic or pain relief effect for at least 5hours that optionally exhibits a decrease in the analgesic or painrelief effect, e.g., as demonstrated in an in-vivo model forpost-operative pain, e.g., from about 5-24 hours followingadministration, see, e.g., Example 8, followed by a period in which thecomposition maintains or regains its analgesic or pain relief effect,from about 1 day to 2 days, days post-administration, such that thecomposition exhibits a long-term the analgesic or pain relief effectfrom about 2 days to about 5 days post-administration, and optionallybeyond, that is at least about 75% or at least about 50% of its averageanalgesic or pain relief effect exhibited from about 1-5 hourspost-administration.

The composition is effective, in one embodiment, to provide measurableplasma concentrations of the amide- or anilide-type local anesthetictype local anesthetic and/or the enolic-acid NSAID for a period of up to5 days following administration.

In a particular embodiment, the composition is effective to release asignificant portion of both the amide- or anilide type local anestheticand the NSAID from the composition, such that 80% by weight or more ofboth drugs are released over a period of about 5 days or up to at leastabout 5 days. In one embodiment, both drugs are released for a period ofbetween at least about 1 day to up to about 5 days, and in anotherembodiment for a period of between about 1-5 days or from about 2-3days, or for at least about 3 days. Although in some cases the amide- oranilide type local anesthetic may be released from the composition inapproximately the same amount and over approximately the same time frameas essentially the same composition further comprising an NSAID, suchas, for example, meloxicam, the incorporation and release of the NSAIDfrom the composition is effective to enhance the efficacy of thelocal-type anesthetic by an amount that exceeds that expected from theincorporation of the NSAID-type drug, such that the effect of the NSAIDon the composition is synergistic rather than additive in nature.

In another aspect, provided is a method of treatment, the methodcomprising dispensing from a needle a composition comprising an amide-or anilide type local anesthetic combined with an NSAID, such as anenolic-acid NSAID, and a polyorthoester, to thereby achieve a controlledrelease of both the local anesthetic and the NSAID from the composition,wherein 80% by weight or more of both drugs are released over a periodof about 5 days.

In another embodiment, the compositions provided herein are for use in amethod of providing local anesthesia to a patient in need thereof. Thetreatment includes administering to a patient a composition as set forthherein, e.g., comprising an amide or anilide-type local anesthetic, anNSAID, and a delivery vehicle, where in some embodiments, the deliveryvehicle is a polyorthoester and the NSAID is an enolic-acid NSAID. Themethod provides rates of release of both the anesthetic and the NSAID,as well as accompanying pharmacokinetic profiles of each effective forreducing or preventing pain over an extended period followingapplication. Local administration can be, e.g., near a nerve, into theepidural space, intrathecal, or directly to a surgical site or to asurgical wound or a non-surgical wound (e.g., instillation, subcutaneousinjection or intradermal injection to a wound area). Subcutaneousinjection to a wound, in some embodiments, is achieved via localinfiltration analgesia (LIA). LIA is an analgesic technique that hasgained popularity since it was first brought to widespread attention byKerr and Kohan in 2008. The technique involves the infiltration of alarge volume dilute solution of a long-acting local anesthetic agent,often with adjuvants (e.g., epinephrine, ketorolac, an opioid),throughout the wound at the time of surgery.

In one embodiment, the extended period is for at least about 5 days. Inanother embodiment, the extended period is for up to about 5 days. Instill another embodiment, the extended period from about 1 day to atleast about 5 days or from about 1 day to up to about 5 days. In yetanother embodiment, the extended period is for about 3 days.

In the methods, in one embodiment, about 80% by weight or more of bothdrugs are released over a period of about 5 days. The composition, inone embodiment, is effective to provide significant pain relief for atleast about 5 days following application.

A method for providing pain relief to a patient in need thereof isprovided, where the method comprises providing a composition asdescribed herein, and instructing that the composition be administeredto the patient to provide pain relief for an extended period. In oneembodiment, the extended period is for at least about 5 days. In anotherembodiment, the extended period is for up to about 5 days. In stillanother embodiment, the extended period from about 1 day to at leastabout 5 days or from about 1 day to up to about 5 days. In yet anotherembodiment, the extended period is for about 3 days.

The compositions and delivery systems provided herein may also be usedfor managing, reducing or treating acute or chronic pain. Thecompositions may also be used for the prophylactic treatment of acute orchronic pain. Acute pain can be associated with, for example, surgery,broken bones, dental work, burns or cuts or labor and childbirth.Chronic pain can be associated with, for example, headache, low backpain, cancer pain, arthritis pain, neurogenic pain and psychogenic pain.

In terms of administration for any of the methods described herein, thecompositions may be injected, instilled, or applied with standardsyringes and needles (e.g., about 16 gauge), or may be applied with,e.g., a spray applicator. The compositions may be injectedsubcutaneously, intradermally or intramuscularly. The compositions maybe applied to a wound topically or subcutaneously. The compositions mayalso be applied perineurally, as described in more detail below. Thecompositions may be applied using various methods known in the art,including by syringe, injectable or tube dispenser.

In one aspect, the compositions described herein which comprise anamide-type local anesthetic and an NSAID are contemplated foradministration as a peripheral nerve block. In particular, thecompositions described above that comprise a triglyceride viscosityreducing agent are contemplated for use as a nerve block. A peripheralnerve block involves the introduction of an agent near or in aperipheral nerve for the reduction of pain or to provide numbness. Typesof peripheral nerve blocks include but are not limited to motor,sensory, differential, and autonomic blocks, and additionally, includebut are not limited to brachial plexus (axillary, interscalene,supraclavicular, infraclavicular), individual upper extremity nerveblocks (median, radial, ulnar, musculocutaneous, axillary), sciatic,ankle, metatarsal, oral, femoral, popliteal fossa, saphenous, distal,digital, deep peroneal, superficial peroneal, tibial, sural, andsaphenous blocks.

In this aspect, injection to a location adjacent to a nerve or nerveplexus requires a composition having a relatively low viscosity (e.g., aviscosity of less than about 5000 mPa-s, 4000 mPa-s, 3000 mPa-s, 2000mPa-s, or 1000 c mPa-s, or between about 250 mPa-s to 5000 mPa-s, 250mPa-s to 3000 mPa-s, 500 mPa-s to 5000 mPa-s, 500 mPa-s to 3000 mPa-s,1000 mPa-s to 3000 mPa-s, 1000 mPa-s to 4000 mPa-s, 1000 mPa-s to 5000mPa-s, 2000 mPa-s to 4000 mPa-s, 1500 mPa-s to 2500 mPa-s, 2500 mPa-s to3500 mPa-s, 3500 mPa-s to 4500 mPa-s, 2750 mPa-s to 3000 mPa-s, 3000mPa-s to 3750 mPa-s, or 3750 mPa-s to 4000 mPa-s when measured at roomtemperature (about 25° C.). One means for reducing the viscosity of aformulation is to prepare the composition using about 40 wt % to 60 wt%, 45 wt % to 55 wt %, 50 wt % to 60 wt %, or 50 wt % to 55 wt % ofpolyorthoester, such as Formula I, about 2% to 10%, 3% to 10%, 2% to 5%,3% to 5%, 2% to 4%, 3% to 4%, or 3% to 8% of a polar aprotic solvent,and about 25 wt % to 45 wt %, 30 wt % to 45 wt %, 35 wt % to 45 wt %, or35 wt % to 40 wt % of triacetin. The polar aprotic solvent which may beused includes but is not limited to DMSO and NMP. The compositionfurther includes an amide-type local anesthetic and an amide-type localanesthetic and a non-steroidal anti-inflammatory drug (NSAID) at a totalwt % of about 1 wt % to 12 wt %, or of about 2 wt % to 7 wt %. Forexample, the composition can include 1.25 wt % to 10 wt % bupivacaineand 0.075 wt % to 1.5 wt % meloxicam. To prepare the composition foradministration as a nerve block, the appropriate amount of amide- oramino-anilide-type local anesthetic is dissolved into a polar aproticsolvent and mixed until dissolved. In one embodiment, the anesthetic isdissolved in the aprotic solvent at a temperature between about 60° C.to 85° C. or at about 70° C. An organic acid, for example, maleic acid,is then added and dissolved, followed by addition of the NSAID, forexample, meloxicam. The appropriate amounts of polymer and triacetin aremixed separately and heated (e.g., at between about 60° C. to 80° C. orat 70° C.) and thoroughly mixed. The solution containing the NSAID andanesthetic is then combined with the desired amount of polymer andtriacetin blend, and then mixed at an elevated temperature untilhomogeneous.

Addition of the triacetin to the composition comprising the amide-typelocal anesthetic and NSAID (e.g., bupivacaine and meloxicam) is shownherein (see, e.g., Example 9 and Example 13) to reduce the viscosity ofthe composition, thereby making it more suitable for a nerve blockinjection. Studies to measure blood levels of active agent released by anerve block formulation show minimal effects of triacetin on thepharmacokinetic profile of the drug delivery composition. In otherwords, an unexpected benefit arose from formulating a reduced-viscositycomposition which can be injected as a nerve block, and despite itsreduced viscosity, provides sustained release of the active agents andcorresponding sustained pain relief. In a particular embodiment, theanesthetic is bupivacaine and the NSAID is meloxicam.

EXAMPLES

The following examples are illustrative in nature and are in no wayintended to be limiting.

Methods:

Viscosity measurements were performed using a Brookfield ViscometerDV-II Pro with a CPA-44PSYZ cup and measured at 25° C. and or 37° C.Viscosity measurements of formulations with less than 8,000 cP (mPa·s)were measured at 25° C. using a CPA-40Z spindle and the system wasverified using 1,000 mPa-s silicone oil Brookfield Viscosity Standard.Viscosity measurements for formulations above 8,000 cP (mPa·s) wereevaluated using a CPA-52Z spindle and standardized using the 30,000mPa-s silicone oil Brookfield Viscosity Standard.

Materials:

Each of the illustrative compositions described in Examples 1-13comprises a polyorthoester (POE) of Formula I, comprising 80%triethylene glycol (TEG) and 20% TEG-glycolide (comprising on average 2glycolides per subunit, i.e., TEG-diglycolide). See, e.g., U.S. Pat. No.8,252,305, Example 1(d).

Example 1 Composition Comprising Ropivacaine and a Non-SteroidalAnti-Inflammatory Drug

A composition containing the polyorthoester of Formula I, an aproticsolvent, ropivacaine, and meloxicam was prepared with the amount of eachcomponent set forth in Table 1-1 below. The composition was prepared bydissolving the NSAID into the aprotic solvent at approximately 80° C.and then adding the ropivacaine with heating until dissolved, to form adrug solution. The drug solution was mixed with the polyorthoester at anelevated temperature, until homogeneous.

TABLE 1-1 Melox- Composition Solvent Ropivacaine icam % % ID ID Base % %Polyorthoesters Solvent 8026-01-01 NMP 5.2% 3.6% 61.5% 29.7% *NMP =N-methylpyrrolidone; POE = polyorthoester

Example 2 In Vitro Release of Ropivacaine and Meloxicam from aPolyorthoester Composition

The release of ropivacaine and meloxicam from the composition in Example1 was determined by placing 50 mg of the polymer composition fromExample 1 into a vial filled with 150 mL of phosphate buffered saline(PBS). The vial was then incubated at 37° C. without agitation. At 24hour intervals, 1 mL samples of the PBS were taken from the vial withoutagitation of the solution. Each sample was analyzed by HPLC to determinethe concentration of ropivacaine and meloxicam. The cumulative drugrelease as a function of time from the 50 mg depot was determined.Results are shown in Table 2-1 below.

TABLE 2-1 In Vitro Release of Ropivacaine and Meloxicam CumulativePercent Drug Released for Composition Composition # Drug 24 hrs 48 hrs72 hrs 8026-01-01 Ropivacaine 52.8 88.5 100.0 8026-01-01 Meloxicam 39.085.3 100.0

Example 3 Delivery Systems Comprising Bupivacaine and Diclofenac

Compositions containing between approximately 62-63% polyorthoester ofFormula I, between approximately 15-20% of an aprotic solvent, between10% and 15% bupivacaine base, and 6% to 7.5% diclofenac were prepared.The compositions were prepared by first dissolving an appropriate amountof diclofenac into an appropriate amount of aprotic solvent atapproximately 80° C. and then dissolving bupivacaine into the solution.The drug solution was then mixed with an appropriate amount of polymerat an elevated temperature, until homogeneous. Exemplary compositionsare presented in Table 3-1.

TABLE 3-1 Composition Solvent Wt % Wt % Wt % Wt % ID ID BupivacaineDiclofenac POE Solvent 8026-03-01 NMP 10.2% 6.06% 63.52% 20.22%8026-03-02 NMP 15.0%  7.5%  62.0%  15.5% *NMP = N-methylpyrrolidone; POE= polyorthoester

Example 4 Delivery Systems Comprising Bupivacaine and Meloxicam

Compositions containing between approximately 55% to 67% polyorthoesterof Formula I, between approximately 16% and 32% of an aprotic solvent,9.9% to 15% bupivacaine, and 1.5% to 3.4% meloxicam were prepared. Thecompositions were prepared by first dissolving the appropriate amount ofNSAID into an aprotic solvent at approximately 80° C. and then addingthe appropriate amount of bupivacaine and heating until dissolved. Thedrug solutions were then mixed with the appropriate amount of polymer atan elevated temperature, until homogenous. Exemplary compositions arepresented in Table 4-1.

TABLE 4-1 Composition Solvent Wt % Wt % Maleic Wt % Wt % ID IDBupivacaine Meloxicam Acid POE Solvent 8026-04-01 NMP  9.9%  3.4%   0% 54.6% 32.1% 8026-04-02 NMP 15.0%  1.5%   0%  66.6% 16.9% 8026-04-03 NMP15.0%  3.0%   0%  65.6% 16.4% 8026-04-04 NMP 10.0% 0.75% 1.2% 73.05%  15% 8026-04-05 NMP  5.0% 0.38% 0.6% 79.02%   15% 8026-04-06 NMP  5.0%0.30% 0.6% 79.10%   15% 8026-04-07 NMP  5.0% 0.15% 0.6% 79.25%   15%8026-04-08 NMP  5.0% 0.08% 0.6% 79.32%   15%

Example 5 In Vitro Release of Bupivacaine and Meloxicam from ExemplaryCompositions

The release of bupivacaine and meloxicam from the compositions describedin Example 4 was determined by placing approximately 50 mg to 200 mg ofthe polymer composition into a vial containing 150 mL of phosphatebuffered saline. The vials were incubated at 37° C. with continuousrotation at 60 rpm. At 24 hour intervals, 1 mL samples were taken fromthe vials without any additional agitation of the solution. Each samplewas analyzed by HPLC to determine the concentration of bupivacaine andthe concentration of meloxicam. The cumulative drug release from thedepot was then calculated. The data is shown in Tables 5-1 and 5-2 andindicate release of both drugs over an extended time period of 3 days ormore.

TABLE 5-1 In Vitro Release of Bupivacaine Cumulative Percent BupivacaineReleased for Compositions Composition # 24 hrs 48 hrs 72 hrs 96 hrs 120hrs 144 hrs 168 hrs 8026-04-01  8.81% 28.28% — — 66.12% —  75.06%8026-04-02 14.56% 24.91% 35.04% 43.77% 48.46%  59.76%  66.35% 8026-04-0310.60% 19.69% 27.08% 33.09% 37.89%  42.32%  36.72% 8026-04-04 41.89%66.92% 83.06% 92.86% 97.69% — — 8026-04-05 42.25% 69.83% 91.51% 96.48%89.42% — — 8026-04-06 18.29% 46.38% 72.52% 93.36% 96.95% — — 8026-04-0740.19% 62.61% 84.35% 97.70% 100.32%  100.63% 100.91% 8026-04-08 22.76%48.85% 65.53% 81.66% 97.07% — —

TABLE 5-2 In Vitro Release of Meloxicam Cumulative Percent MeloxicamReleased for Compositions Composition # 24 hrs 48 hrs 72 hrs 96 hrs 120hrs 144 hrs 168 hrs 8026-04-01 16.98% 24.48% — — 66.12% — 72.54%8026-04-02  7.62% 11.43% 17.65% 31.15% 34.35% 38.65% 34.06% 8026-04-0311.71% 19.37% 24.83% 26.11% 27.25% 28.06% 28.21% 8026-04-04 10.97%54.94% 81.11% 96.13% 100.18%  — — 8026-04-05 27.05% 67.45% 93.62% 95.15%96.14% — — 8026-04-06 18.23% 70.17% 69.21% 99.60% 104.01%  — —8026-04-07 13.36% 40.20% 69.94% 93.12% 100.39%  100.98%  100.80% 8026-04-08 41.50% 74.65% 93.51% 98.15% 99.03% — —

Example 6 In Vivo Administration of Bupivacaine—Meloxicam Compositions

In vivo pharmacokinetic studies were conducted as follows. Sheepweighing between 60 and 100 kg received 4 mL of a composition preparedas described in Example 4: composition no. 8026-04-03 (Study 1, n=6),8026-04-04 (Study 2, n=3) or 8026-04-05 (Study 2, n=3). Plasma sampleswere collected from each sheep at the following time points: t=0(immediately prior to drug administration), 0.5, 1, 3, 6, and 8, 24, and30 hours post-administration and then daily for days 3-7 (48 through 168hours). The plasma samples were subsequently analyzed by LC/MS/MS forbupivacaine and meloxicam.

The data from the study is shown in FIGS. 1A-1B, where plasma levels ofbupivacaine (FIG. 1A) and of meloxicam (FIG. 1B) are plotted at eachtime point, for the three compositions—15 wt % bupivacaine/3 wt %meloxicam (closed squares); 10 wt % bupivacaine/0.75 wt % meloxicam(open circles); and 5 wt % bupivacaine/0.38 wt % meloxicam (opentriangles). The data indicates that the compositions provide measurableplasma concentrations of bupivacaine and meloxicam over a period of atleast 96 hours following administration.

Example 7 In Vivo Administration of Bupivacaine—Meloxicam Compositions

An in vivo pharmacokinetic study was conducted as follows. Beagles (n=5)weighing approximately 10 kg received 1 mL of Composition ID No.8026-04-07 (Example 4) in two separate injections of approximately 0.5mL each. Plasma samples were collected from each dog at the followingtime points: t=0 (immediately prior to drug administration), 0.5, 1, 3,6, 24, and daily up to day 5 (120 hrs). The plasma samples weresubsequently analyzed by LC/MS/MS for bupivacaine and meloxicam.

The data from the study are illustrated in FIGS. 2A-2B and indicate thatthe compositions provide measurable plasma concentrations of bupivacaineand meloxicam over a period of at least 96 hours followingadministration.

Example 8 In Vivo Pharmacodynamics of Bupivacaine—Meloxicam Compositions

Various compositions were evaluated for their capacity to reducepost-surgical incisional (post-operative or POP) pain in a porcine modelsystem. In this model, a 7 cm long skin and fascia incision was made inthe left flank under general anesthesia. Test composition or controlarticle was applied to the wound. The skin incision was then closedusing sterile sutures. All studies described below evaluated 4 pigs pergroup.

Post-operative pain was assessed using the Von Frey methodology. VonFrey filaments (Ugo Basile) were applied at approximately ˜0.5 cmproximal to the incision line to the surface of the flank skin.Filaments of increasing diameter (thicker fibers equate to a higher gramforce while thinner fibers equate to a lower gram force) were applieduntil the animal withdrew from the stimuli (the act of moving away fromthe stimuli). Each filament was applied 3-5 times. If withdrawal was notachieved, a thicker filament was applied. The maximum force filament was60 g. If a withdrawal was achieved, a thinner filament was applied. Byalternating the filament thickness, the gram force required to achievewithdrawal reaction was determined and recorded. The greater the forcethat was applied, the more effective the analgesia.

Example 8A

Study 1 evaluated compositions containing bupivacaine or ropivacaineabsent an enolic-acid NSAID. An extended release polymer compositioncontaining 15% bupivacaine was compared to an extended release polymercomposition containing 5% ropivacaine. The compositions were preparedfollowing the procedure described in Example 1. Following creation of anincision (n=4 pigs/group), each test composition was administered byinstilling directly onto the surface of the wound area or by injectingsubcutaneously into the lateral margins of the wound. The doses were 2mL of saline (Group 1), 2 mL of 15% bupivacaine composition (Groups 2and 3), and 1.8 mL of 5% ropivacaine composition (Groups 4 and 5). Table8-1 summaries the test groups and compositions. Analgesia was evaluatedby response in the von Frey test, as described above. The baseline(pre-surgery) withdrawal score for the von Frey test was 60 g.

TABLE 8-1 Composition of Vehicle Control and Test Articles (Study 1)Vehicle Method Dose API Composition Group of Administration Volume (%)POE % NMP % 1 Subcutaneous 2.0 Saline Control Injection Around Wound 2Subcutaneous 2.0 Bupivacaine 55% 30% Injection Around (15%) Wound 3 Laidonto Wound 2.0 Surface 4 Subcutaneous 1.8 Ropivacaine 71% 24% InjectionAround (5%) Wound 5 Laid onto Wound 1.8 Surface

The von Frey response for the animals in each test group is shown inFIG. 3, where withdrawal force, in gram force is shown as a function oftime, in hours and days, after administration in vivo to pigs. The testcompositions are denoted as follows: (i) 15 wt % bupivacaineadministered by injection (vertical dashes fill) or by instillation(vertical line fill) or (ii) 5 wt % ropivacaine administered byinjection (horizontal line fill) or instillation (diamond crosshatchfill); and bars with dotted fill represent the response for the controlgroup treated with saline.

Example 8B

A second study (Study 2) was performed to compare extended releaseformulations containing a local amide-type anesthetic to formulationscontaining local anesthetics in combination with non-steroidalanti-inflammatory drugs. The nociceptive activity of five differentformulations was evaluated in the pig POP model. The compositions arepresented in Table 8-2. Extended release formulations containingropivacaine (slower release and faster release, Groups 2 and 3respectively) were compared to extended release formulations containingbupivacaine and the NSAIDs diclofenac and meloxicam, Groups 4 and 5respectively. A dose volume of 2 mL for vehicle or test article wasinjected subcutaneously into the lateral margins of the incision and theincision closed with sutures. Assessment of nociception by von Freymethod at baseline, 1, 3, and 5 hours, and days 1 through 6 aftersurgery as was described above.

TABLE 8-2 Comparative Compositions used in Study 2 Vehicle MaleicComposition API Acid POE NMP Group (%) Wt % wt % wt % 1 Saline Control 2Ropivacaine (5.0) N/A 0.6% 75.5% 18.9% 3 Ropivacaine (5.0) N/A 0.2%71.1% 23.7% 4 Bupivacaine (15.0) Diclofenac 0 57.5%   20% (7.5) 5Bupivacaine (15.0) Meloxicam 0 61.5%   20% (3.5)

Results of Study 2 are shown in FIG. 4, where withdrawal force, in gramforce is shown as a function of time, in hours and days, afteradministration by subcutaneous injection to a wound incision in vivo inpigs, where the test compositions are denoted as follows: (i) 5 wt %ropivacaine with 0.6% maleic acid (horizontal line fill), (ii) 5 wt %ropivacaine with 0.2% maleic acid (diamond crosshatch fill), (iii) 15 wt% bupivacaine and 7.5 wt % diclofenac (vertical dashes fill), or (iv) 15wt % bupivacaine and 3.5 wt % meloxicam (vertical line fill); and barswith dotted fill represent the response for the control group treatedwith saline.

Example 8C

A third study, Study 3, was conducted to evaluate five differentformulations containing different concentrations of the two activeingredients, bupivacaine and meloxicam. As in the previous studies, 2 mLof each formulation was administered either by 1) subcutaneous injectionaround the wound margins (8 injections; 4/side) or 2) by directapplication to the wound surface created by the incision or 3) injectedinto the tissues on either side of the wound. The parameters evaluatedand the timing for the assessment were the same as in Study 2. Table 8-3presents the compositions tested.

TABLE 8-3 Composition Tested (Study 3) API Vehicle CompositionBupivacaine Meloxicam POE NMP Maleic Group (%) (%) (%) (%) Acid Group 110.0 0.75 74.25 15 1.2 Group 2 10.0 0.38 73.42 15 1.2 Group 3 5.0 0.7578.65 15 0.6 Group 4 15.0 1.50 66.7 15 1.8 Group 5 5.0 0.38 79.02 15 0.6

The results showed that all bupivacaine/meloxicam compositionsdemonstrated good analgesia through Day 6 consistent with the previousstudy (data not shown). There was no significant benefit to bupivacaineconcentrations greater than 5%. A dose response for meloxicam was notobserved.

Example 8D

Compositions containing 5% bupivacaine with varying concentrations ofmeloxicam ranging from 0.08 to 0.4% were tested, along with acomposition containing meloxicam alone (i.e., containing no localanesthetic). For the meloxicam-only composition, meloxicam was dissolvedin a water/t-butyl alcohol mixture and the pH was adjusted to 11. Thesolution was then lyophilized. The appropriate amount of lyophilizedmeloxicam was dissolved in an aprotic solvent, DMSO, at approximately80° C. The resultant drug solution was then mixed with the appropriateamount of polymer at an elevated temperature until homogeneous.Additionally, compositions containing 5% ropivacaine with and withoutmeloxicam were also evaluated to determine if the synergistic effect ofmeloxicam and bupivacaine extended to other local anesthetics.

The compositions tested and group assignments are presented in Table8-4. All test compositions were administered to pigs as subcutaneousinjections into both sides of the incision (8 injections; 4/side) at atotal dose of 2 mL. The parameters evaluated and the timing for theassessment were the same as in Study 2.

TABLE 8-4 Composition of Vehicle Control and Test Articles API VehicleComposition Bupivacaine Ropivacaine Meloxicam POE NMP Maleic Acid Group(%) (%) (%) (%) (%) (%) 1 5.0 — 0.19 79.21 15.0 0.60 2 5.0 — 0.08 79.3215.0 0.60 3 5.0 — 0.30 79.10 15.0 0.60 4 — — 0.16 84.84 15 — 5 — 5.00.38 72.45 22.0 0.17 6 — 5.0 — 72.75 22.0 0.25

Results are shown in FIGS. 5A-5B, where withdrawal force, in gram force,is shown as a function of time, in hours and days, after administrationof the test formulations, denoted as follows: compositions comprised ofa polyorthoester delivery vehicle and 5 wt % bupivacaine in combinationwith meloxicam at 0.08 wt % (vertical dash fill), 0.19 wt % meloxicam(vertical line fill), and 0.3 wt % meloxicam (horizontal line fill), acomposition comprised of a polyorthoester delivery vehicle and 0.15 wt %meloxicam alone (dotted fill) (FIG. 5A) and compositions comprised of apolyorthoester delivery vehicle and 5 wt % ropivacaine in combinationwith 0.38 wt % meloxicam (diamond crosshatch fill) or with 5 wt %ropivacaine alone (no fill; open bars).

Example 9 Polymer Compositions Comprising Bupivacaine and Meloxicam anda Viscosity Reducing Triglyceride

The composition identified as 8026-04-07 in Example 4 was prepared toinclude 30% triacetin (glycerol triacetate) and assigned identificationno. 8026-09-01. Viscosity of the triacetin-containing composition wasmeasured as set forth in the Methods section above and was 7,115 mPa-sat 25° C. Viscosity of a similar composition with no triacetin wasapproximately 75,000 mPa-s at 25° C. when measured as set forth in theMethods section above.

TABLE 9-1 Composition Wt % Wt % Wt % Wt % Maleic Wt % ID NMP TriacetinBupivacaine Meloxicam Acid Polyorthoester 8026-04-07    15% N/A 5.0%0.15% 0.6% 79.25% 8026-09-01 11.57% 23.05 3.86 0.12 0.46 60.94

The composition with the triglyceride viscosity reducing agent wascompared to the composition with no triglyceride viscosity reducingagent in a canine pharmacokinetic study. The in vivo pharmacokineticstudy was conducted as follows. Beagles (n=5), weighing approximately 10kg, received 1 mL of composition identification no. 8026-04-07 in twoseparate injections of approximately 0.5 mL. A separate set of beagles(n=5), also weighing approximately 10 kg, received 1.3 mL of compositionidentification no. 8026-09-01 in two separate injections ofapproximately 0.65 mL each (total of 1.3 mL). Plasma samples werecollected from each dog at the following time points: t=0 (immediatelyprior to drug administration), 1, 3, 6, 8, 24, and 34 to 36 hourspost-administration, and then daily for days 3-7 (48 through 168 hours).The plasma samples were subsequently analyzed by LC/MS/MS forbupivacaine and meloxicam.

The data from the study is shown in FIGS. 6A-6B. The data indicates thatthe compositions provide very similar plasma PK profiles with only asmall increase in Cmax for the composition comprising a triglycerideviscosity reducing agent (open circles) in relation to the compositionlacking the triglyceride viscosity reducing agent (triangles).

Example 10 Polymer Compositions Comprising Bupivacaine and Meloxicam anda Viscosity Reducing Agent

Compositions containing between approximately 40% to 60% polyorthoesterof Formula I, between approximately 3% and 10% of a polar aproticsolvent (NMP or DMSO), 2.5% to 5.0% bupivacaine, and 0.075% to 0.15%meloxicam were prepared. The compositions were prepared by dissolvingbupivacaine into the aprotic solvent at approximately 80° C. and mixinguntil dissolved. Maleic acid was then added and dissolved, followed bythe addition of meloxicam, with continued mixing until dissolved, toform a drug solution. Separately, the polymer and triacetin (glyceroltriacetate) were combined and heated to 70° C. then thoroughly mixed.The drug solution was then combined with the polymer and triacetin blendat an elevated temperature and mixed until homogeneous. Viscosity of thecompositions was measured as set forth in the Methods section above.Exemplary compositions are presented in Table 10-1.

TABLE 10-1 Wt % Viscosity Composition Wt % Wt % Maleic Wt % Wt % Wt %mPa-s # Bupivacaine Meloxicam Acid POE Solvent Triacetin (25° C.)8026-10-01 2.5% 0.075% 0.15% 54.2  3% 40% 3890 NMP 8026-10-02 2.5%0.075% 0.10% 52.3  5% 40% 2006 DMSO 8026-10-03 2.5% 0.15% 0.15% 54.2% 8% 35% 2876 DMSO 8026-10-04 5.0% 0.15% 0.15% 49.7% 10% 35% 1794 DMSO8026-10-05 2.5% 0.15% 0.15% 57.2% 10% 30% 4522 DMSO 8026-10-06 2.5%0.075% 0.15% 54.3%  8% 35% 3105 DMSO 8026-10-07 2.5% 0.075% 0.075%57.35% 10% 30% 3131 DMSO 8026-10-08 2.5% 0.075% 0.05% 62.38% 10% 25%8519 DMSO 8026-10-09 5.0% 0.15% 0.4% 59.45% 10% 25% N/A DMSO 8026-10-105.0% 0.15% 0.4% 53.10% 10% 30% 4876 DMSO

The addition of the triglyceride viscosity reducing agent triacetin tothese compositions decreased the viscosity at least 10-fold, at least20-fold, or at least 40-fold, or more, as compared to compositions withno triglyceride viscosity reducing agent.

Example 11 In Vitro Release of Bupivacaine and Meloxicam fromCompositions Comprising a Triglyceride Viscosity Reducing Agent

The release of bupivacaine and meloxicam from the compositions ofExample 10 was determined by placing 100 mg of the polymer composition(approximately 50 mg to 200 mg) into vials containing 200 mL ofphosphate buffered saline. The vials were incubated at 37° C. on ashaker at 60 RPM. At 24 hour intervals, 1 mL samples were taken from thevials without any agitation of the solution. Each sample was analyzed byHPLC to determine the concentration of bupivacaine and meloxicam. Thecumulative drug release from the depot was then calculated and is shownin Tables 11-1 and 11-2.

TABLE 11-1 In Vitro Release of Bupivacaine Percent Bupivacaine Releasedfor Compositions Composition # 24 hrs 48 hrs 72 hrs 8026-10-01 29.13%58.94% 75.66% 8026-10-02 24.48% 45.16% 76.25% 8026-10-03 28.92% 51.95%74.48% 8026-10-04 8.06% 24.21% 46.55% 8026-10-05 20.08% 47.04% 70.51%8026-10-07 25.51% 55.48% 72.66% 8026-10-08 16.60% 44.00% 63.90%8026-10-10 22.83% 47.25% 74.02%

TABLE 11-2 In Vitro Release of Meloxicam Percent Meloxicam Released forCompositions Composition # 24 hrs 48 hrs 72 hrs 8026-10-01 37.30% 64.83%91.20% 8026-10-02 28.86% 51.79% 84.05% 8026-10-03 41.52% 74.59% 99.35%8026-10-04 9.44% 33.17% 57.59% 8026-10-05 30.30% 67.09% 89.30%8026-10-07 41.37% 70.87% 83.86% 8026-10-08 33.60% 58.40% 76.70%8026-10-10 20.63% 44.18% 66.71%

Example 12 In Vivo Analysis of Delivery Systems Comprising Bupivacaineand Meloxicam and a Triglyceride Viscosity Reducing Agent

An in vivo pharmacokinetic study was conducted as follows. Beagles (n=5)weighing approximately 10 kg received 2 mL of composition identifiednos. 8026-10-03 and 8026-10-05 in two separate injections ofapproximately 1 mL each. Plasma samples were collected from each dog atthe following time points: t=0, (immediately prior to drugadministration), 0.5, 1, 3, 6, 24, and daily up to day 5 (120 hrs). Theplasma samples were subsequently analyzed by LC/MS/MS for bupivacaineand meloxicam.

The data from the study is shown in FIGS. 7A-7B. The compositionsprovided measurable plasma concentrations of bupivacaine (FIG. 7A) andmeloxicam (FIG. 7B) over a period of at least 96 hours followingadministration, where the composition with 35 wt % triacetin(8026-10-03) is indicated by the triangles and the composition with 30wt % triacetin (8026-10-05) is represented by the open circles.

Example 13 In Vivo Use of the Compositions as a Nerve Block

A study was performed to determine if the combination of an amide-typelocal anesthetic such as bupivacaine and an NSAID as described hereincould be used for local anesthesia by way of a nerve block procedure. Inorder to conduct a perineural injection, the lower viscosityformulations, such as those described in Example 10, were evaluated.

The efficacy of the compositions were tested using the Von Frey assay,however, in these studies, as compared to the postoperative painstudies, no incisions were made. Four grams of each composition wereinjected into each of 4 animals and administered so as to be near thesciatic nerve in one flank of the pig. Table 13-1 below provides asummary of the compositions injected to each animal.

TABLE 13-1 Wt % Composition Wt % Wt % Maleic Wt % Solvent Wt % Group #Bupivacaine Meloxicam Acid POE Wt % Triacetin 1 Saline — — — — — — 2Bupivacaine 0.5% — — — — — Injection (5 mL) 3 8026-10-01 2.5% 0.075%0.15% 54.20% NMP 40% 3% 4 8026-13-01 2.5% N/A 0.10% 54.35% NMP 40% 3% 58026-10-02 2.5% 0.075% 0.10% 52.33% DMSO 40% 5%

Nerve Block Assessment: To assess the degree of nerve block, Von Freyfilaments (Ugo Basile) are applied at the dorsal source surface of thefoot. As the gram number of filaments increases, the force on the dorsalfoot skin increases. The maximum force is 300 g. Filaments are applieduntil the animal withdraws from the stimuli. Each filament is applied3-5 times. If withdrawal is not achieved, a thicker filament is applied.If a withdrawal is achieved, a thinner filament is applied (thicker orthinner refers to higher/thicker or lower/thinner gram force). Byalternating the filament thickness, the force required to achievewithdrawal reaction is determined and recorded. Withdrawal reaction isconsidered as the act of lifting the leg and moving away from thestimuli.

The results of the Von Frey assay are presented in FIG. 8, wherewithdrawal force, in gram force, is shown as a function of time, inhours and days, after administration in vivo to pigs of compositionscomprised of a polyorthoester delivery vehicle, 2.5 wt % bupivacainealone (Group 4, 8026-13-01, vertical dashes fill) or 2.5 wt %bupivacaine, 0.0175 wt % meloxicam and 0.15% maleic acid (Group 3,8026-10-01, vertical line fill) or 0.10 wt % maleic acid (Group 5,8026-0-02, horizontal line fill), or a buffered solution of 0.5 wt %bupivacaine (no fill; open bars, Group 2); bars with dotted fillrepresent the response for the control group treated with saline.

Example 14 Preparation of Compositions Comprising Granisetron and aTriglyceride Viscosity Reducing Agent

Compositions containing between approximately 65 wt % to 88 wt %polyorthoester of Formula I, between approximately 5 wt % and 10 wt % ofan polar aprotic solvent (NMP or DMSO), between approximately 0 wt % and20 wt % triacetin, and approximately 2 wt % granisetron were prepared.The compositions were prepared by adding the granisetron into an aproticsolvent at approximately 80° C. mixing until dissolved to form a drugsolution. Separately, the polymer and triacetin (glycerol triacetate)were combined and heated to 70° C. followed by thorough mixing. The drugsolution was then combined with the polymer and triacetin blend at 70°C. and mixed until homogeneous. For comparison, a granisetronformulation consisting of 15% of a polar aprotic solvent was prepared.

Viscosity of the compositions was measured at 25° C. and at 37° C. usingthe method set forth in the Methods section above. Results are shown inTable 14-1. The addition of triacetin to the compositions decreased theviscosity when measured at 25° C. by at least about 5 fold (compare8026-14-06 and 8026-14-03), at least about 7-fold (compare 8016-14-01and 8026-14-02), at least about 20 fold (compare 8026-14-04 and8025-14-03) or at least about 90-fold (compare 8026-14-05 and8026-14-03). The addition of triacetin to the compositions decreased theviscosity when measured at 37° C. by at least about 5 fold (compare8026-14-01 and 8026-14-02; and 8026-14-03 and 8026-14-03), at leastabout 30-fold (compare 8026-14-05 and 8026-14-03).

TABLE 14-1 Viscosity Viscosity Formulation Wt % Wt % Solvent Triacetin25° C. 37° C. ID Granisetron POE Wt % Wt % (mPa-s) (mPa-s) 8026-14-012.00% 88.00% DMSO  0.00% 672,242 149,401 10.00%  8026-14-02 2.00% 78.00%DMSO 10.00% 93,506 35,228 10.00%  8026-14-03 2.00% 93.00% NMP  0.00%5,712,695 490,174 5.00% 8026-14-04 2.00% 78.00% NMP 10.00% 330,85978,205 5.00% 8026-14-05 2.00% 73.00% NMP 20.00% 62,520 17,745 5.00%8026-14-06 2.00% 88.00% NMP  5.00% 1,028,656 192,472 5.00% 8026-14-072.00% 78.00% NMP 15.00% 120,342 31,592 5.00% 8026-14-08 2.00% 83.00% NMP 0.00% 90,232 26,202 15.00% 

Example 15 In Vitro Release of Compositions Comprising Granisetron and aTriglyceride Viscosity Reducing Agent

The release of granisetron from the compositions of Example 14 wasdetermined by placing 200 mg of each composition into a vial containing150 mL of phosphate buffered saline. The samples were then incubated at37° C. on a shaker at 60 RPM for the first 24 hours and then incubatedat 50° C. for 120 hours. At 24 hour intervals, 1 mL samples were takenfrom the vials without any agitation of the solution. Each sample wasanalyzed by HPLC to determine the concentration of granisetron. Thecumulative drug release from each depot was calculated and is shown inTable. 15-1.

TABLE 15-1 In Vitro Release of Granisetron Percent Granisetron ReleasedComposition # 24 hrs 48 hrs 72 hrs 96 hrs 8026-14-01 4.10% 13.7% 46.0%91.1% 8026-14-02 5.90% 20.6% 43.2% 77.5% 8026-14-03 6.50% 28.2% 52.7%81.2% 8026-14-04 6.80% 34.6% 57.9% 88.8% 8026-14-05 17.50%  54.7% 70.8%86.6% 8026-14-06 6.60% 31.7% 58.4% 79.9% 8026-14-08 10.4% 46.6% 80.9%101.3

The compositions provided release of granisetron for at least about 3days or at least about 4 days. The addition of triacetin to reduceviscosity of the compositions did not alter the in vitro release ofgranisetron relative to a similar composition lacking triacetin, as seenwhen comparing composition number 8026-14-03, with no triacetin, and8026-14-04, with 10% triacetin. Release of granisetron from thetriacetin composition (which had a 17 fold lower viscosity at 25° C.)was within 10% of the granisetron cumulative release provided by asimilar composition lacking the triacetin. Similarly, a comparison of8026-14-01 (with no triacetin) and 8026-14-02 (with 10 wt % triacetin)reveals that the triacetin-containing composition with a 7-fold lowerviscosity at 25° C. released granisetron at a rate within about 15% ofthe release provided by the composition with no triacetin at the 24hour, 72 hour and 96 hour time points.

It is claimed:
 1. A delivery system for administration to a subject, thedelivery system comprising: 40 wt % to 75 wt % of a polyorthoester; 3 wt% to 25 wt % dimethyl sulfoxide; 10 wt % to 35 wt % triacetin; 2 wt % to5 wt % bupivacaine; and 0.01 wt % to 1 wt % meloxicam.
 2. The deliverysystem of claim 1, wherein the polyorthoester is represented by thestructure shown as Formula I:

where R* is C1-4 alkyl, n ranges from 5 to 400, and A is a diol.
 3. Thedelivery system of claim 2, where A is R¹ or R³, where the fraction of Aunits that are of formula R¹ is between 0 and 25 mole percent, R¹ is

p and q are each independently integers ranging from between about 1 and20 and the average number of p or the average sum of p and q is betweenabout 1 and 7, and R⁵ is H or methyl, R⁶ is

where s is an integer from 0 to 10, and R³ is

where x is an integer ranging from 1 to
 10. 4. The delivery system ofclaim 1, wherein the composition has a viscosity less than 10000 mPa-swhen measured at 37° C. using a viscometer.
 5. The delivery system ofclaim 1, wherein the fraction of A units that are of formula R¹ is about20 mole percent.
 6. The delivery system of claim 1, wherein R³ and R⁶are both —(CH₂—CH₂—O)₂—(CH₂—CH₂)—; R⁵ is H; and p is 1 or
 2. 7. Thedelivery system of claim 6, wherein R⁵ is hydrogen.
 8. The deliverysystem of claim 2, wherein when A is R¹ is

R⁵ is H, and R⁶ is

where the resulting polyorthoester comprises the subunit

where the sum of p and q is, on average, 2 and s is 2, and when A is R³,x is
 2. 9. The delivery system of claim 8, wherein the fraction of Aunits that are of formula R¹ is about 20 percent.
 10. The deliverysystem of claim 1, wherein the polyorthoester has a weight averagemolecular weight between 2,500 daltons and 10,000 daltons.
 11. Thedelivery system of claim 1, wherein the bupivacaine and the meloxicamare solubilized in a single phase.
 12. The delivery system of claim 1,wherein the delivery system is an extended-release composition.
 13. Thedelivery system of claim 1, further comprising maleic acid.
 14. A methodfor providing analgesia or pain relief to a subject in need thereof,comprising: administering to the subject the delivery system accordingto claim
 1. 15. The method of claim 14, wherein the delivery system isadministered as a nerve block.
 16. The method of claim 14, wherein thedelivery system is administered as a peripheral nerve block.
 17. Themethod of claim 14, wherein the delivery system is administered to asurgical wound.
 18. The method according to claim 14, wherein the painis post-operative pain.
 19. A method for prophylactic treatment of painin a subject, comprising: administering to the subject the deliverysystem according to claim 1.